molecules-logo

Journal Browser

Journal Browser

Recent Trends on Enzymes Inhibitors and Activators in Drug Research 3.0

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 46981

Special Issue Editor

Special Issue Information

Dear Colleagues,

The human body is composed of thousands of different enzymes, many of them acting in concert in order to maintain homeostasis. On the other hand, many pathological conditions such as inflammation, diabetes, microbial infections, HIV, and neoplastic diseases are the result of enzyme involvement. Diseases may arise due to the malfunctioning of a particular enzyme or due to imbalanced regulation of enzyme reaction pathways. On the other hand, bacterial, fugal, or viral enzymes are crucial for infection of microorganisms and for the progression of infectious diseases. Consequently, inhibition of a specific enzyme is a big challenge for the treatment of various diseases. Although enzyme inhibition is universally accepted as a strategy to treat the above-mentioned conditions, the development and use of specific inhibitors need to counteract several difficulties mostly related with the fact that most body functions take place through a cascade of enzyme reactions and that in most cases a great number of isoenzymes exist, participating in different biochemical pathways. All this makes clear that designing a drug molecule that can selectively inhibit a particular isoenzyme in order to lead to a therapeutic benefit is not an easy goal. The study of enzyme crystal structures and active site environments, site directed mutagenesis of the catalytic residue, computer-aided molecular docking experiments, and the use of sophisticated assays are some of the strategies used in drug design. Thus, the design of potent enzyme inhibitors is a crucial step in the long-lasting process of novel drug design and development. Nowadays, with the COVID-19 pandemic, there is an urgent need for design of new, safe protease inhibitors to attenuate the disease. This current Special Issue aims to present the recent tendencies in the development of inhibitors of different types of enzymes, including reverse transcriptase, integrase, gyrase, MurB, cyclooxygenase-1/cyclooxygenase-2 (COX-1/COX-2.), lipoxygenase (LOX), aldose reductase, protein tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor (PPR-γ), Mpro, thymidylate kinase, carbonic anhydrase and many others.

We encourage you to contribute to this scientific program by submitting your papers for this Special Issue of Molecules entitled “Recent Trends on Enzymes Inhibitors and Activators in Drug Research 3.0”.

Prof. Dr. Athina Geronikaki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Enzymes
  • PTP1B
  • COX/LOX
  • HIV
  • COVID-19
  • Drug design

Related Special Issue

Published Papers (42 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Editorial

Jump to: Research, Review

5 pages, 193 KiB  
Editorial
Recent Trends in Enzyme Inhibition and Activation in Drug Design
by Athina Geronikaki
Molecules 2021, 26(1), 17; https://doi.org/10.3390/molecules26010017 - 22 Dec 2020
Cited by 11 | Viewed by 2452
Abstract
It is known that enzymes are involved in many pathological conditions, such as inflammation, diabetes, microbial infections, HIV, neoplastic, neglected diseases and others [...] Full article

Research

Jump to: Editorial, Review

26 pages, 3632 KiB  
Article
New Hybrid Tetrahydropyrrolo[3,2,1-ij]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation
by Nadezhda P. Novichikhina, Alexander S. Shestakov, Svetlana M. Medvedeva, Anna M. Lagutina, Mikhail Yu. Krysin, Nadezhda A. Podoplelova, Mikhail A. Panteleev, Ivan S. Ilin, Alexey V. Sulimov, Anna S. Tashchilova, Vladimir B. Sulimov, Athina Geronikaki and Khidmet S. Shikhaliev
Molecules 2023, 28(9), 3851; https://doi.org/10.3390/molecules28093851 - 01 May 2023
Cited by 4 | Viewed by 1320
Abstract
Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, [...] Read more.
Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa. For the synthesis of new hybrid derivatives of pyrrolo[3,2,1-ij]quinoline-2-one, we used a convenient structural modification of the tetrahydroquinoline fragment by varying the substituents in positions 2, 4, and 6. In addition, the design of target molecules was achieved by alkylating the amino group of the rhodanine fragment with propargyl bromide or by replacing the rhodanine fragment with 2-thioxoimidazolidin-4-one. The in vitro testing showed that eight derivatives are capable of inhibiting both coagulation factors, two compounds are selective inhibitors of factor Xa, and two compounds are selective inhibitors of factor XIa. Overall, these data indicate the potential anticoagulant activity of these molecules through the inhibition of the coagulation factors Xa and XIa. Full article
Show Figures

Figure 1

8 pages, 1420 KiB  
Communication
Discovery of a Novel Trifluoromethyl Diazirine Inhibitor of SARS-CoV-2 Mpro
by Andrea Citarella, Davide Moi, Martina Pedrini, Helena Pérez-Peña, Stefano Pieraccini, Claudio Stagno, Nicola Micale, Tanja Schirmeister, Giulia Sibille, Giorgio Gribaudo, Alessandra Silvani, Daniele Passarella and Clelia Giannini
Molecules 2023, 28(2), 514; https://doi.org/10.3390/molecules28020514 - 04 Jan 2023
Cited by 4 | Viewed by 1992
Abstract
SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the [...] Read more.
SARS-CoV-2 Mpro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of Mpro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several Mpro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 Mpro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 Mpro at a low micromolar level (IC50 = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PLpro revealed lack of inhibition, assuring the selectivity of the compound for the Mpro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells’ viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 Mpro binders. Full article
Show Figures

Figure 1

16 pages, 5042 KiB  
Article
Expression and Molecular Modification of Chitin Deacetylase from Streptomyces bacillaris
by Lili Yin, Qi Wang, Jianan Sun and Xiangzhao Mao
Molecules 2023, 28(1), 113; https://doi.org/10.3390/molecules28010113 - 23 Dec 2022
Cited by 3 | Viewed by 1392
Abstract
Chitin deacetylase can be used in the green and efficient preparation of chitosan from chitin. Herein, a novel chitin deacetylase SbCDA from Streptomyces bacillaris was heterologously expressed and comprehensively characterized. SbDNA exhibits its highest deacetylation activity at 35 °C and pH [...] Read more.
Chitin deacetylase can be used in the green and efficient preparation of chitosan from chitin. Herein, a novel chitin deacetylase SbCDA from Streptomyces bacillaris was heterologously expressed and comprehensively characterized. SbDNA exhibits its highest deacetylation activity at 35 °C and pH 8.0. The enzyme activity is enhanced by Mn2+ and prominently inhibited by Zn2+, SDS, and EDTA. SbCDA showed better deacetylation activity on colloidal chitin, (GlcNAc)5, and (GlcNAc)6 than other forms of the substrate. Molecular modification of SbCDA was conducted based on sequence alignment and homology modeling. A mutant SbCDA63G with higher activity and better temperature stability was obtained. The deacetylation activity of SbCDA63G was increased by 133% compared with the original enzyme, and the optimal reaction temperature increased from 35 to 40 °C. The half-life of SbCDA63G at 40 °C is 15 h, which was 5 h longer than that of the original enzyme. The improved characteristics of the chitin deacetylase SbCDA63G make it a potential candidate to industrially produce chitosan from chitin. Full article
Show Figures

Figure 1

9 pages, 1495 KiB  
Article
Computational Prediction of Inhibitors and Inducers of the Major Isoforms of Cytochrome P450
by Anastassia Rudik, Alexander Dmitriev, Alexey Lagunin, Dmitry Filimonov and Vladimir Poroikov
Molecules 2022, 27(18), 5875; https://doi.org/10.3390/molecules27185875 - 10 Sep 2022
Cited by 3 | Viewed by 1475
Abstract
Human cytochrome P450 enzymes (CYPs) are heme-containing monooxygenases. This superfamily of drug-metabolizing enzymes is responsible for the metabolism of most drugs and other xenobiotics. The inhibition of CYPs may lead to drug–drug interactions and impair the biotransformation of drugs. CYP inducers may decrease [...] Read more.
Human cytochrome P450 enzymes (CYPs) are heme-containing monooxygenases. This superfamily of drug-metabolizing enzymes is responsible for the metabolism of most drugs and other xenobiotics. The inhibition of CYPs may lead to drug–drug interactions and impair the biotransformation of drugs. CYP inducers may decrease the bioavailability and increase the clearance of drugs. Based on the freely available databases ChEMBL and PubChem, we have collected over 70,000 records containing the structures of inhibitors and inducers together with the IC50 values for the inhibitors of the five major human CYPs: 1A2, 3A4, 2D6, 2C9, and 2C19. Based on the collected data, we developed (Q)SAR models for predicting inhibitors and inducers of these CYPs using GUSAR and PASS software. The developed (Q)SAR models could be applied for assessment of the interaction of novel drug-like substances with the major human CYPs. The created (Q)SAR models demonstrated reasonable accuracy of prediction. They have been implemented in the web application P450-Analyzer that is freely available via the Internet. Full article
Show Figures

Figure 1

11 pages, 690 KiB  
Article
Proanthocyanidins Modulate Rumen Enzyme Activities and Protein Utilization In Vitro
by Sultan Singh, Pushpendra Koli, Brijesh K. Bhadoria, Manjree Agarwal, Suman Lata, Yonglin Ren and Xin Du
Molecules 2022, 27(18), 5870; https://doi.org/10.3390/molecules27185870 - 10 Sep 2022
Cited by 4 | Viewed by 1064
Abstract
This study investigated the principal leaf protein (rubisco) solubilization and in vitro ruminal enzyme activity in relation to the molecular structure of proanthocyanidins extracted from leaves of Anogeissus pendula and Eugenia jambolana. Six proanthocyanidin fractions were extracted by 50% (v/ [...] Read more.
This study investigated the principal leaf protein (rubisco) solubilization and in vitro ruminal enzyme activity in relation to the molecular structure of proanthocyanidins extracted from leaves of Anogeissus pendula and Eugenia jambolana. Six proanthocyanidin fractions were extracted by 50% (v/v) methanol–water followed by 70% (v/v) acetone–water and then distilled water from leaves of A. pendula (AP) and E. jambolana (EJ) to yield EJ–70, EJ–50, EJ–DW, AP–70, AP–50 and AP–DW. Fractions were examined for their molecular structure and their effects on sheep ruminal enzymes and solubilization of rubisco in vitro. All fractions significantly (p < 0.05) inhibited the activity of ruminal glutamic oxaloacetic transaminase and glutamic pyruvic transaminase. The fractions AP–50 and EJ–50 significantly inhibited the activity of the R-cellulase enzyme. Most of the fractions inhibited R-glutamate dehydrogenase activity (p < 0.05) by increasing its concentration, while protease activity decreased by up to 58% with increasing incubation time and concentration. The solubilization of rubisco was observed to be comparatively higher in A. pendula (16.60 ± 1.97%) and E. jambolana (15.03 ± 1.06%) than that of wheat straw (8.95 ± 0.95%) and berseem hay (3.04 ± 0.08%). A significant (p < 0.05) increase in protein solubilization was observed when wheat straw and berseem hay were supplemented with A. pendula and E. jambolana leaves at different proportions. The efficiency of microbial protein was significantly (p < 0.05) greater with the supplementation of leaves of A. pendula in comparison to E. jambolana. The overall conclusion is that the proanthocyanidins obtained from E. jambolana exhibited greater inhibitory activities on rumen enzymes, whereas A. pendula recorded higher protein solubilization. Thus, PAs from A. pendula and E. jambolana appear to have the potential to manipulate rumen enzyme activities for efficient utilization of protein and fiber in ruminants. Full article
Show Figures

Figure 1

22 pages, 1300 KiB  
Article
New Chemicals Suppressing SARS-CoV-2 Replication in Cell Culture
by Alexey Sulimov, Ivan Ilin, Danil Kutov, Khidmet Shikhaliev, Dmitriy Shcherbakov, Oleg Pyankov, Nadezhda Stolpovskaya, Svetlana Medvedeva and Vladimir Sulimov
Molecules 2022, 27(17), 5732; https://doi.org/10.3390/molecules27175732 - 05 Sep 2022
Cited by 4 | Viewed by 1841
Abstract
Candidates to being inhibitors of the main protease (Mpro) of SARS-CoV-2 were selected from the database of Voronezh State University using molecular modeling. The database contained approximately 19,000 compounds represented by more than 41,000 ligand conformers. These ligands were [...] Read more.
Candidates to being inhibitors of the main protease (Mpro) of SARS-CoV-2 were selected from the database of Voronezh State University using molecular modeling. The database contained approximately 19,000 compounds represented by more than 41,000 ligand conformers. These ligands were docked into Mpro using the SOL docking program. For one thousand ligands with best values of the SOL score, the protein–ligand binding enthalpy was calculated by the PM7 quantum-chemical method with the COSMO solvent model. Using the SOL score and the calculated protein–ligand binding enthalpies, eighteen compounds were selected for the experiments. Several of these inhibitors suppressed the replication of the coronavirus in cell culture, and we used the best three among them in the search for chemical analogs. Selection among analogs using the same procedure followed by experiments led to identification of seven inhibitors of the SARS-CoV-2 replication in cell culture with EC50 values at the micromolar level. The identified inhibitors belong to three chemical classes. The three inhibitors, 4,4-dimethyldithioquinoline derivatives, inhibit SARS-CoV-2 replication in Vero E6 cell culture just as effectively as the best published non-covalent inhibitors, and show low cytotoxicity. These results open up a possibility to develop antiviral drugs against the SARS-CoV-2 coronavirus. Full article
Show Figures

Graphical abstract

13 pages, 2058 KiB  
Article
Sequential Extraction of Proanthocyanidin Fractions from Ficus Species and Their Effects on Rumen Enzyme Activities In Vitro
by Pushpendra Koli, Sultan Singh, Brijesh K. Bhadoria, Manjree Agarwal, Suman Lata and Yonglin Ren
Molecules 2022, 27(16), 5153; https://doi.org/10.3390/molecules27165153 - 12 Aug 2022
Cited by 7 | Viewed by 1134
Abstract
Three proanthocyanidin fractions per species were sequentially extracted by 50% (v/v) methanol–water, 70% (v/v) acetone–water, and distilled water from leaves of Ficus racemosa (fractions FR) and F. religiosa (fractions FRL) to yield fractions FR-50, FR-70, [...] Read more.
Three proanthocyanidin fractions per species were sequentially extracted by 50% (v/v) methanol–water, 70% (v/v) acetone–water, and distilled water from leaves of Ficus racemosa (fractions FR) and F. religiosa (fractions FRL) to yield fractions FR-50, FR-70, FR-DW, FRL-50, FRL-70, and FRL-DW. Fractions were examined for their molecular structure, effect on ruminal enzyme activities, and principal leaf protein (Rubisco) solubilization in vitro. All fractions except FRL-70 contained flavonoids including (+) catechin, (−) epicatechin, (+) gallocatechin, (−) epigallocatechin, and their -4-phloroglucinol adducts. The fractions FRL-50 and FRL-DW significantly (p < 0.05) inhibited the activity of ruminal glutamic oxaloacetic transaminase and glutamic pyruvic transaminase. All fractions inhibited glutamate dehydrogenase activity (p < 0.05) with increasing concentration, while protease activity decreased 15–18% with increasing concentrations. Fractions FRL-50 and FRL-DW completely inhibited the activity of cellulase enzymes. Solubilization of Rubisco was higher in F. religiosa (22.36 ± 1.24%) and F. racemosa (17.26 ± 0.61%) than that of wheat straw (WS) (8.95 ± 0.95%) and berseem hay (BH) (3.04 ± 0.08%). A significant (p < 0.05) increase in protein solubilization was observed when WS and BH were supplemented with FR and FRL leaves at different proportions. The efficiency of microbial protein was significantly (p < 0.05) greater in diets consisting of WS and BH with supplementation of F. racemosa leaves in comparison to those supplemented with F. religiosa leaves. The overall conclusion is that the fractions extracted from F. religiosa showed greater inhibitory effects on rumen enzymes and recorded higher protein solubilization in comparison to the F. racemosa. Thus, PAs from F. religiosa are potential candidates to manipulate rumen enzymes activities for efficient utilization of protein and fiber in ruminants. Full article
Show Figures

Figure 1

18 pages, 5061 KiB  
Article
Assessing the Role of a Malonamide Linker in the Design of Potent Dual Inhibitors of Factor Xa and Cholinesterases
by Rosa Purgatorio, Nicola Gambacorta, Francesco Samarelli, Gianfranco Lopopolo, Modesto de Candia, Marco Catto, Orazio Nicolotti and Cosimo D. Altomare
Molecules 2022, 27(13), 4269; https://doi.org/10.3390/molecules27134269 - 02 Jul 2022
Cited by 6 | Viewed by 1430
Abstract
The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to [...] Read more.
The rational discovery of new peptidomimetic inhibitors of the coagulation factor Xa (fXa) could help set more effective therapeutic options (to prevent atrial fibrillation). In this respect, we explored the conformational impact on the enzyme inhibition potency of the malonamide bridge, compared to the glycinamide one, as a linker connecting the P1 benzamidine anchoring moiety to the P4 aryl group of novel selective fXa inhibitors. We carried out structure–activity relationship (SAR) studies aimed at investigating para- or meta-benzamidine as the P1 basic group as well as diversely decorated aryl moieties as P4 fragments. To this end, twenty-three malonamide derivatives were synthesized and tested as inhibitors of fXa and thrombin (thr); the molecular determinants behind potency and selectivity were also studied by employing molecular docking. The malonamide linker, compared to the glycinamide one, does significantly increase anti-fXa potency and selectivity. The meta-benzamidine (P1) derivatives bearing 2′,4′-difluoro-biphenyl as the P4 moiety proved to be highly potent reversible fXa-selective inhibitors, achieving inhibition constants (Ki) in the low nanomolar range. The most active compounds were also tested against cholinesterase (ChE) isoforms (acetyl- or butyrylcholinesterase, AChE, and BChE), and some of them returned single-digit micromolar inhibition potency against AChE and/or BChE, both being drug targets for symptomatic treatment of mild-to-moderate Alzheimer’s disease. Compounds 19h and 22b were selected as selective fXa inhibitors with potential as multimodal neuroprotective agents. Full article
Show Figures

Figure 1

16 pages, 4673 KiB  
Article
Novel Inhibitors of 2′-O-Methyltransferase of the SARS-CoV-2 Coronavirus
by Alexey Sulimov, Danil Kutov, Ivan Ilin, Yibei Xiao, Sheng Jiang and Vladimir Sulimov
Molecules 2022, 27(9), 2721; https://doi.org/10.3390/molecules27092721 - 23 Apr 2022
Cited by 6 | Viewed by 1706
Abstract
The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O [...] Read more.
The COVID-19 pandemic is still affecting many people worldwide and causing a heavy burden to global health. To eliminate the disease, SARS-CoV-2, the virus responsible for the pandemic, can be targeted in several ways. One of them is to inhibit the 2′-O-methyltransferase (nsp16) enzyme that is crucial for effective translation of viral RNA and virus replication. For methylation of substrates, nsp16 utilizes S-adenosyl methionine (SAM). Binding of a small molecule in the protein site where SAM binds can disrupt the synthesis of viral proteins and, as a result, the replication of the virus. Here, we performed high-throughput docking into the SAM-binding site of nsp16 for almost 40 thousand structures, prepared for compounds from three libraries: Enamine Coronavirus Library, Enamine Nucleoside Mimetics Library, and Chemdiv Nucleoside Analogue Library. For the top scoring ligands, semi-empirical quantum-chemical calculations were performed, to better estimate protein–ligand binding enthalpy. Relying upon the calculated binding energies and predicted docking poses, we selected 21 compounds for experimental testing. Full article
Show Figures

Figure 1

16 pages, 11204 KiB  
Article
Development of New Thiophene-Containing Triaryl Pyrazoline Derivatives as PI3Kγ Inhibitors
by Bing Yang, Bo Zhang, Qun Zhao, Jin Li and Yujun Shi
Molecules 2022, 27(8), 2404; https://doi.org/10.3390/molecules27082404 - 08 Apr 2022
Viewed by 1373
Abstract
A series of new thiophene-containing triaryl pyrazoline derivatives, 3a3t, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of [...] Read more.
A series of new thiophene-containing triaryl pyrazoline derivatives, 3a3t, were synthesized and evaluated regarding PI3K inhibition activity and anti-tumor potency based on a trial of introducing significant moieties, including pyrazoline and thiophene, and simplifying the parallel ring structures. Most of the tested compounds indicated potent PI3K inhibitory potency, with this series of compounds showing more potency for PI3Kγ than PI3Kα. The top hit 3s seemed more potent than the positive control LY294002 on inhibiting PI3Kγ (IC50 values: 0.066 μM versus 0.777 μM) and more selective from PI3Kα (Index values: 645 versus 1.74). It could be inferred that the combination of para- and meta-, as well as the modification of the electron-donating moieties, led to the improvement in potency. The anti-proliferation inhibitory activity and the enzymatic inhibition potency indicated consistent tendencies. The top hit 3s could inhibit the phosphorylation of Akt by inhibiting PI3K through the PI3K-Akt-mTOR pathway. The molecular docking simulation indicated that the binding pattern of 3s into PI3Kγ was preferable than that of PI3Kα, with more hydrogen bond, more π-involved interactions, and fewer π-sulfur interactions. The information in this work is referable for the further development of selective inhibitors for specific isoforms of PI3K. Full article
Show Figures

Figure 1

14 pages, 2559 KiB  
Article
Thiazole/Thiadiazole/Benzothiazole Based Thiazolidin-4-One Derivatives as Potential Inhibitors of Main Protease of SARS-CoV-2
by Anthi Petrou, Panagiotis Zagaliotis, Nikoleta F. Theodoroula, George A. Mystridis, Ioannis S. Vizirianakis, Thomas J. Walsh and Athina Geronikaki
Molecules 2022, 27(7), 2180; https://doi.org/10.3390/molecules27072180 - 28 Mar 2022
Cited by 17 | Viewed by 2802
Abstract
Since the time of its appearance until present, COVID-19 has spread worldwide, with over 71 million confirmed cases and over 1.6 million deaths reported by the World Health Organization (WHO). In addition to the fact that cases of COVID-19 are increasing worldwide, the [...] Read more.
Since the time of its appearance until present, COVID-19 has spread worldwide, with over 71 million confirmed cases and over 1.6 million deaths reported by the World Health Organization (WHO). In addition to the fact that cases of COVID-19 are increasing worldwide, the Delta and Omicron variants have also made the situation more challenging. Herein, we report the evaluation of several thiazole/thiadiazole/benzothiazole based thiazolidinone derivatives which were chosen from 112 designed derivatives by docking as potential molecules to inhibit the main protease of SARS-CoV-2. The contained experimental data revealed that among the fifteen compounds chosen, five compounds (k3, c1, n2, A2, A1) showed inhibitory activity with IC50 within the range of 0.01–34.4 μΜ. By assessing the cellular effects of these molecules, we observed that they also had the capacity to affect the cellular viability of human normal MRC-5 cells, albeit with a degree of variation. More specifically, k3 which is the most promising compound with the higher inhibitory capacity to SARS-CoV-2 protease (0.01 μΜ) affects in vitro cellular viability only by 57% at the concentration of 0.01 μM after 48 h in culture. Overall, these data provide evidence on the potential antiviral activity of these molecules to inhibit the main protease of SARS-CoV-2, a fact that sheds light on the chemical structure of the thiazole/thiadiazole/benzothiazole based thiazolidin-4-one derivatives as potential candidates for COVID-19 therapeutics. Full article
Show Figures

Graphical abstract

18 pages, 4745 KiB  
Article
Design, Synthesis, and Evaluation of Novel 2H-Benzo[b][1,4]thiazin-3(4H)-one Derivatives as New Acetylcholinesterase Inhibitors
by Sazan Haji Ali, Derya Osmaniye, Begüm Nurpelin Sağlık, Serkan Levent, Yusuf Özkay and Zafer Asım Kaplancıklı
Molecules 2022, 27(7), 2121; https://doi.org/10.3390/molecules27072121 - 25 Mar 2022
Cited by 5 | Viewed by 2161
Abstract
Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The [...] Read more.
Alzheimer’s disease (AD) is a slowly progressive neurodegenerative disease that causes dementia in people aged 65 and over. In the present study, a series of thiadiazole hybrid compounds with benzothiazine derivatives as acetylcholinesterase inhibitors were developed and evaluated for their biological activity. The AChE and BChE inhibition potentials of all compounds were evaluated by using the in vitro Ellman method. The biological evaluation showed that compounds 3i and 3j displayed significant inhibitory activity against AChE. Compounds 3i and 3j showed IC50 values of 0.027 µM and 0.025 µM against AChE, respectively. The reference drug donepezil (IC50 = 0.021 µM) also showed significant inhibition against AChE. Further docking simulation also revealed that these compounds (3i and 3j) interacted with the active site of the enzyme similarly to donepezil. The antioxidant study revealed that compounds 3i and 3j exhibited greater antioxidant effects. An in vitro blood–brain barrier permeability study showed that compounds 3i and 3j are promising compounds against AD. The cytotoxicity study of compounds 3i and 3j showed non-cytotoxic with an IC50 value of 98.29 ± 3.98 µM and 159.68 ± 5.53 µM against NIH/3T3 cells, respectively. Full article
Show Figures

Figure 1

18 pages, 2101 KiB  
Article
Enhancement of the Anti-Inflammatory Activity of NSAIDs by Their Conjugation with 3,4,5-Trimethoxybenzyl Alcohol
by Paraskevi Tziona, Panagiotis Theodosis-Nobelos, Georgios Papagiouvannis, Anthi Petrou, Chryssoula Drouza and Eleni A. Rekka
Molecules 2022, 27(7), 2104; https://doi.org/10.3390/molecules27072104 - 24 Mar 2022
Cited by 5 | Viewed by 1786
Abstract
The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified [...] Read more.
The synthesis of derivatives of three nonspecific COX-1 and COX-2 inhibitors, ibuprofen, ketoprofen, naproxen is presented. These acids were connected via an amide bond with an amino acid (L-proline, L-tyrosine, and beta-alanine) used as a linker. The amino acid carboxylic group was esterified with 3,4,5 trimethoxybenzyl alcohol. The activity of the novel derivatives was examined in vivo on carrageenan-induced inflammation, and in vitro, as cyclooxygenase and lipoxygenase inhibitors. It was found that the new compounds were more potent anti-inflammatory agents than the parent drugs. Thus, the ibuprofen (21) and ketoprofen (16) derivatives reduced rat paw edema by 67 and 91% (the reduction by the relevant NSAIDs was 36 and 47%, respectively). They inhibited COX-2 more than the starting drugs (21 by 67%, ibuprofen 46%, 19 by 94%, ketoprofen 49%). Docking of compounds on the active sites of COX-1 and COX-2 reflects their in vitro activity. Thus, 19 adopts an unfavorable orientation for COX-1 inhibition, but it binds effectively in the binding pocket of COX-2, in agreement with the absence of activity for COX-1 and the high inhibition of COX-2. In conclusion, the performed structural modifications result in the enhancement of the anti-inflammatory activity, compared with the parent NSAIDs. Full article
Show Figures

Graphical abstract

18 pages, 2809 KiB  
Article
New Blood Coagulation Factor XIIa Inhibitors: Molecular Modeling, Synthesis, and Experimental Confirmation
by Anna Tashchilova, Nadezhda Podoplelova, Alexey Sulimov, Danil Kutov, Ivan Ilin, Mikhail Panteleev, Khidmet Shikhaliev, Svetlana Medvedeva, Nadezhda Novichikhina, Andrey Potapov and Vladimir Sulimov
Molecules 2022, 27(4), 1234; https://doi.org/10.3390/molecules27041234 - 12 Feb 2022
Cited by 13 | Viewed by 2285
Abstract
In the modern world, complications caused by disorders in the blood coagulation system are found in almost all areas of medicine. Thus, the development of new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis is an urgent task. The [...] Read more.
In the modern world, complications caused by disorders in the blood coagulation system are found in almost all areas of medicine. Thus, the development of new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis is an urgent task. The blood coagulation factor XIIa is one of the most promising therapeutic targets for the development of anticoagulants based on its inhibitors. The initial stage of drug development is directly related to computational methods of searching for a lead compound. In this study, docking followed by quantum chemical calculations was used to search for noncovalent low-molecular-weight factor XIIa inhibitors in a focused library of druglike compounds. As a result of the study, four low-molecular-weight compounds were experimentally confirmed as factor XIIa inhibitors. Selectivity testing revealed that two of the identified factor XIIa inhibitors were selective over the coagulation factors Xa and XIa. Full article
Show Figures

Figure 1

17 pages, 2862 KiB  
Article
Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors
by Andrea Angeli, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Volodymyr Brovarets, Roman Vydzhak, Svitlana Panchishin, Athina Geronikaki and Claudiu T. Supuran
Molecules 2021, 26(22), 7023; https://doi.org/10.3390/molecules26227023 - 20 Nov 2021
Cited by 9 | Viewed by 2138
Abstract
A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic [...] Read more.
A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs. Full article
Show Figures

Figure 1

15 pages, 5718 KiB  
Article
Discovery of Novel Tankyrase Inhibitors through Molecular Docking-Based Virtual Screening and Molecular Dynamics Simulation Studies
by Vladimir P. Berishvili, Alexander N. Kuimov, Andrew E. Voronkov, Eugene V. Radchenko, Pradeep Kumar, Yahya E. Choonara, Viness Pillay, Ahmed Kamal and Vladimir A. Palyulin
Molecules 2020, 25(14), 3171; https://doi.org/10.3390/molecules25143171 - 11 Jul 2020
Cited by 18 | Viewed by 3763
Abstract
Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, [...] Read more.
Tankyrase enzymes (TNKS), a core part of the canonical Wnt pathway, are a promising target in the search for potential anti-cancer agents. Although several hundreds of the TNKS inhibitors are currently known, identification of their novel chemotypes attracts considerable interest. In this study, the molecular docking and machine learning-based virtual screening techniques combined with the physico-chemical and ADMET (absorption, distribution, metabolism, excretion, toxicity) profile prediction and molecular dynamics simulations were applied to a subset of the ZINC database containing about 1.7 M commercially available compounds. Out of seven candidate compounds biologically evaluated in vitro for their inhibition of the TNKS2 enzyme using immunochemical assay, two compounds have shown a decent level of inhibitory activity with the IC50 values of less than 10 nM and 10 μM. Relatively simple scores based on molecular docking or MM-PBSA (molecular mechanics, Poisson-Boltzmann, surface area) methods proved unsuitable for predicting the effect of structural modification or for accurate ranking of the compounds based on their binding energies. On the other hand, the molecular dynamics simulations and Free Energy Perturbation (FEP) calculations allowed us to further decipher the structure-activity relationships and retrospectively analyze the docking-based virtual screening performance. This approach can be applied at the subsequent lead optimization stages. Full article
Show Figures

Figure 1

15 pages, 1826 KiB  
Communication
Data and Text Mining Help Identify Key Proteins Involved in the Molecular Mechanisms Shared by SARS-CoV-2 and HIV-1
by Olga Tarasova, Sergey Ivanov, Dmitry A. Filimonov and Vladimir Poroikov
Molecules 2020, 25(12), 2944; https://doi.org/10.3390/molecules25122944 - 26 Jun 2020
Cited by 10 | Viewed by 3594
Abstract
Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is [...] Read more.
Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation. Full article
Show Figures

Figure 1

17 pages, 5976 KiB  
Article
Alvaxanthone, a Thymidylate Synthase Inhibitor with Nematocidal and Tumoricidal Activities
by Piotr Maj, Mattia Mori, Justyna Sobich, Joanna Markowicz, Łukasz Uram, Zbigniew Zieliński, Deborah Quaglio, Andrea Calcaterra, Ylenia Cau, Bruno Botta and Wojciech Rode
Molecules 2020, 25(12), 2894; https://doi.org/10.3390/molecules25122894 - 23 Jun 2020
Cited by 2 | Viewed by 2668
Abstract
With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. [...] Read more.
With the aim to identify novel inhibitors of parasitic nematode thymidylate synthase (TS), we screened in silico an in-house library of natural compounds, taking advantage of a model of nematode TS three-dimensional (3D) structure and choosing candidate compounds potentially capable of enzyme binding/inhibition. Selected compounds were tested as (i) inhibitors of the reaction catalyzed by TSs of different species, (ii) agents toxic to a nematode parasite model (C. elegans grown in vitro), (iii) inhibitors of normal human cell growth, and (iv) antitumor agents affecting human tumor cells grown in vitro. The results pointed to alvaxanthone as a relatively strong TS inhibitor that causes C. elegans population growth reduction with nematocidal potency similar to the anthelmintic drug mebendazole. Alvaxanthone also demonstrated an antiproliferative effect in tumor cells, associated with a selective toxicity against mitochondria observed in cancer cells compared to normal cells. Full article
Show Figures

Graphical abstract

22 pages, 9726 KiB  
Article
1-(1-Arylethylpiperidin-4-yl)thymine Analogs as Antimycobacterial TMPK Inhibitors
by Yanlin Jian, Fabian Hulpia, Martijn D. P. Risseeuw, He Eun Forbes, Guy Caljon, Hélène Munier-Lehmann, Helena I. M. Boshoff and Serge Van Calenbergh
Molecules 2020, 25(12), 2805; https://doi.org/10.3390/molecules25122805 - 17 Jun 2020
Cited by 4 | Viewed by 2221
Abstract
A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold [...] Read more.
A series of Mycobacterium tuberculosis TMPK (MtbTMPK) inhibitors based on a reported compound 3 were synthesized and evaluated for their capacity to inhibit MtbTMPK catalytic activity and the growth of a virulent M. tuberculosis strain (H37Rv). Modifications of the scaffold of 3 failed to afford substantial improvements in MtbTMPK inhibitory activity and antimycobacterial activity. Optimization of the substitution pattern of the D ring of 3 resulted in compound 21j with improved MtbTMPK inhibitory potency (three-fold) and H37Rv growth inhibitory activity (two-fold). Moving the 3-chloro substituent of 21j to the para-position afforded isomer 21h, which, despite a 10-fold increase in IC50-value, displayed promising whole cell activity (minimum inhibitory concentration (MIC) = 12.5 μM). Full article
Show Figures

Graphical abstract

20 pages, 7066 KiB  
Article
In Silico Evaluation of the Effectivity of Approved Protease Inhibitors against the Main Protease of the Novel SARS-CoV-2 Virus
by Phaedra Eleftheriou, Dionysia Amanatidou, Anthi Petrou and Athina Geronikaki
Molecules 2020, 25(11), 2529; https://doi.org/10.3390/molecules25112529 - 29 May 2020
Cited by 55 | Viewed by 6417
Abstract
The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has [...] Read more.
The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than −8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia. Full article
Show Figures

Graphical abstract

16 pages, 3442 KiB  
Article
Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa
by Nadezhda Novichikhina, Ivan Ilin, Anna Tashchilova, Alexey Sulimov, Danil Kutov, Irina Ledenyova, Mikhail Krysin, Khidmet Shikhaliev, Anna Gantseva, Ekaterina Gantseva, Nadezhda Podoplelova and Vladimir Sulimov
Molecules 2020, 25(8), 1889; https://doi.org/10.3390/molecules25081889 - 19 Apr 2020
Cited by 22 | Viewed by 3466
Abstract
Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of [...] Read more.
Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor. Full article
Show Figures

Graphical abstract

19 pages, 1280 KiB  
Article
2-(Arylamino)-6-(trifluoromethyl)nicotinic Acid Derivatives: New HIV-1 RT Dual Inhibitors Active on Viral Replication
by Angela Corona, Valentina Onnis, Claudia Del Vecchio, Francesca Esposito, Yung-Chi Cheng and Enzo Tramontano
Molecules 2020, 25(6), 1338; https://doi.org/10.3390/molecules25061338 - 15 Mar 2020
Cited by 10 | Viewed by 3819
Abstract
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of [...] Read more.
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects. Full article
Show Figures

Figure 1

25 pages, 15058 KiB  
Article
1,2,4-Triazolo[1,5-a]pyrimidines as a Novel Class of Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Activity
by Jenny Desantis, Serena Massari, Angela Corona, Andrea Astolfi, Stefano Sabatini, Giuseppe Manfroni, Deborah Palazzotti, Violetta Cecchetti, Christophe Pannecouque, Enzo Tramontano and Oriana Tabarrini
Molecules 2020, 25(5), 1183; https://doi.org/10.3390/molecules25051183 - 05 Mar 2020
Cited by 22 | Viewed by 4351
Abstract
Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of [...] Read more.
Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (IIIB strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors. Full article
Show Figures

Graphical abstract

12 pages, 2928 KiB  
Article
(Q)SAR Models of HIV-1 Protein Inhibition by Drug-Like Compounds
by Leonid A. Stolbov, Dmitry S. Druzhilovskiy, Dmitry A. Filimonov, Marc C. Nicklaus and Vladimir V. Poroikov
Molecules 2020, 25(1), 87; https://doi.org/10.3390/molecules25010087 - 25 Dec 2019
Cited by 4 | Viewed by 2825
Abstract
Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict [...] Read more.
Despite the achievements of antiretroviral therapy, discovery of new anti-HIV medicines remains an essential task because the existing drugs do not provide a complete cure for the infected patients, exhibit severe adverse effects, and lead to the appearance of resistant strains. To predict the interaction of drug-like compounds with multiple targets for HIV treatment, ligand-based drug design approach is widely applied. In this study, we evaluated the possibilities and limitations of (Q)SAR analysis aimed at the discovery of novel antiretroviral agents inhibiting the vital HIV enzymes. Local (Q)SAR models are based on the analysis of structure–activity relationships for molecules from the same chemical class, which significantly restrict their applicability domain. In contrast, global (Q)SAR models exploit data from heterogeneous sets of drug-like compounds, which allows their application to databases containing diverse structures. We compared the information for HIV-1 integrase, protease and reverse transcriptase inhibitors available in the EBI ChEMBL, NIAID HIV/OI/TB Therapeutics, and Clarivate Analytics Integrity databases as the sources for (Q)SAR training sets. Using the PASS and GUSAR software, we developed and validated a variety of (Q)SAR models, which can be further used for virtual screening of new antiretrovirals in the SAVI library. The developed models are implemented in the freely available web resource AntiHIV-Pred. Full article
Show Figures

Graphical abstract

16 pages, 2865 KiB  
Article
Chasing ChEs-MAO B Multi-Targeting 4-Aminomethyl-7-Benzyloxy-2H-Chromen-2-ones
by Mariagrazia Rullo, Marco Catto, Antonio Carrieri, Modesto de Candia, Cosimo Damiano Altomare and Leonardo Pisani
Molecules 2019, 24(24), 4507; https://doi.org/10.3390/molecules24244507 - 09 Dec 2019
Cited by 13 | Viewed by 2834
Abstract
A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor ( [...] Read more.
A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes. Full article
Show Figures

Graphical abstract

18 pages, 6824 KiB  
Article
Synthesis and Antiviral Activity of Novel 1,3,4-Thiadiazole Inhibitors of DDX3X
by Annalaura Brai, Stefania Ronzini, Valentina Riva, Lorenzo Botta, Claudio Zamperini, Matteo Borgini, Claudia Immacolata Trivisani, Anna Garbelli, Carla Pennisi, Adele Boccuto, Francesco Saladini, Maurizio Zazzi, Giovanni Maga and Maurizio Botta
Molecules 2019, 24(21), 3988; https://doi.org/10.3390/molecules24213988 - 04 Nov 2019
Cited by 31 | Viewed by 4156
Abstract
The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase [...] Read more.
The human ATPase/RNA helicase X-linked DEAD-box polypeptide 3 (DDX3X) emerged as a novel therapeutic target in the fight against both infectious diseases and cancer. Herein, a new family of DDX3X inhibitors was designed, synthesized, and tested for its inhibitory action on the ATPase activity of the enzyme. The potential use of the most promising derivatives it has been investigated by evaluating their anti-HIV-1 effects, revealing inhibitory activities in the low micromolar range. A preliminary ADME analysis demonstrated high metabolic stability and good aqueous solubility. The promising biological profile, together with the suitable in vitro pharmacokinetic properties, make these novel compounds a very good starting point for further development. Full article
Show Figures

Graphical abstract

7 pages, 837 KiB  
Article
Prediction of Severity of Drug-Drug Interactions Caused by Enzyme Inhibition and Activation
by Alexander Dmitriev, Dmitry Filimonov, Alexey Lagunin, Dmitry Karasev, Pavel Pogodin, Anastasiya Rudik and Vladimir Poroikov
Molecules 2019, 24(21), 3955; https://doi.org/10.3390/molecules24213955 - 31 Oct 2019
Cited by 12 | Viewed by 2882
Abstract
Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition [...] Read more.
Drug-drug interactions (DDIs) severity assessment is a crucial problem because polypharmacy is increasingly common in modern medical practice. Many DDIs are caused by alterations of the plasma concentrations of one drug due to another drug inhibiting and/or inducing the metabolism or transporter-mediated disposition of the victim drug. Accurate assessment of clinically relevant DDIs for novel drug candidates represents one of the significant tasks of contemporary drug research and development and is important for practicing physicians. This work is a development of our previous investigations and aimed to create a model for the severity of DDIs prediction. PASS program and PoSMNA descriptors were implemented for prediction of all five classes of DDIs severity according to OpeRational ClassificAtion (ORCA) system: contraindicated (class 1), provisionally contraindicated (class 2), conditional (class 3), minimal risk (class 4), no interaction (class 5). Prediction can be carried out both for known drugs and for new, not yet synthesized substances using only their structural formulas. Created model provides an assessment of DDIs severity by prediction of different ORCA classes from the first most dangerous class to the fifth class when DDIs do not take place in the human organism. The average accuracy of DDIs class prediction is about 0.75. Full article
Show Figures

Figure 1

18 pages, 5038 KiB  
Article
Novel Hit Compounds as Putative Antifungals: The Case of Aspergillus fumigatus
by Eftichia Kritsi, Minos-Timotheos Matsoukas, Constantinos Potamitis, Anastasia Detsi, Marija Ivanov, Marina Sokovic and Panagiotis Zoumpoulakis
Molecules 2019, 24(21), 3853; https://doi.org/10.3390/molecules24213853 - 25 Oct 2019
Cited by 19 | Viewed by 3022
Abstract
The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely [...] Read more.
The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely used category for the treatment of fungal infections. However, increasingly, azole-resistant strains constitute a major problem to be faced. Towards this direction, our study focused on the identification of compounds bearing novel structural motifs which may evolve as a new class of antifungals. To fulfil this scope, a combination of in silico techniques and in vitro assays were implemented. Specifically, a ligand-based pharmacophore model was created and served as a 3D search query to screen the ZINC chemical database. Additionally, molecular docking and molecular dynamics simulations were used to improve the reliability and accuracy of virtual screening results. In total, eight compounds, bearing completely different chemical scaffolds from the commercially available azoles, were proposed and their antifungal activity was evaluated using in vitro assays. Results indicated that all tested compounds exhibit antifungal activity, especially compounds 1, 2, and 4, which presented the most promising minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values and, therefore, could be subjected to further hit to lead optimization. Full article
Show Figures

Graphical abstract

29 pages, 4991 KiB  
Article
Novel Thiazolidin-4-ones as Potential Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase
by Anthi Petrou, Phaedra Eleftheriou, Athina Geronikaki, Melpomeni G. Akrivou and Ioannis Vizirianakis
Molecules 2019, 24(21), 3821; https://doi.org/10.3390/molecules24213821 - 23 Oct 2019
Cited by 23 | Viewed by 3411
Abstract
Background: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research [...] Read more.
Background: HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the treatment of AIDS. Although, many compounds are already being used as anti-HIV drugs, research for the development of new inhibitors continues as the virus develops resistant strains. Methods: The best features of available NNRTIs were taken into account for the design of novel inhibitors. PASS (Prediction of activity spectra for substances) prediction program and molecular docking studies for the selection of designed compounds were used for the synthesis. Compounds were synthesized using conventional and microwave irradiation methods and HIV RT inhibitory action was evaluated by colorimetric photometric immunoassay. Results: The evaluation of HIV-1 RT inhibitory activity revealed that seven compounds have significantly lower ΙC50 values than nevirapine (0.3 μΜ). It was observed that the activity of compounds depends not only on the nature of substituent and it position in benzothiazole ring but also on the nature and position of substituents in benzene ring. Conclusion: Twenty four of the tested compounds exhibited inhibitory action lower than 4 μΜ. Seven of them showed better activity than nevirapine, while three of the compounds exhibited IC50 values lower than 5 nM. Two compounds 9 and 10 exhibited very good inhibitory activity with IC50 1 nM. Full article
Show Figures

Graphical abstract

29 pages, 13077 KiB  
Article
Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches
by Katalin Szilágyi, István Hajdú, Beáta Flachner, Zsolt Lőrincz, Júlia Balczer, Péter Gál, Péter Závodszky, Chiara Pirli, Balázs Balogh, István M. Mándity, Sándor Cseh and György Dormán
Molecules 2019, 24(20), 3641; https://doi.org/10.3390/molecules24203641 - 09 Oct 2019
Cited by 11 | Viewed by 3748
Abstract
The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since [...] Read more.
The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively. Full article
Show Figures

Figure 1

12 pages, 2296 KiB  
Article
Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation
by Victor Kartsev, Athina Geronikaki, Silvia Bua, Alessio Nocentini, Anthi Petrou, Boris Lichitsky, Mykhaylo Frasinyuk, Janis Leitans, Andris Kazaks, Kaspars Tars and Claudiu T. Supuran
Molecules 2019, 24(19), 3580; https://doi.org/10.3390/molecules24193580 - 04 Oct 2019
Cited by 6 | Viewed by 2579
Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, [...] Read more.
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets. Full article
Show Figures

Figure 1

12 pages, 2159 KiB  
Article
Active Anti-Inflammatory and Hypolipidemic Derivatives of Lorazepam
by Panagiotis Theodosis-Nobelos, Georgios Papagiouvannis, Panos N. Kourounakis and Eleni A. Rekka
Molecules 2019, 24(18), 3277; https://doi.org/10.3390/molecules24183277 - 09 Sep 2019
Cited by 14 | Viewed by 3366
Abstract
Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic [...] Read more.
Novel derivatives of some non steroidal anti-inflammatory drugs, as well as of the antioxidants α-lipoic acid, trolox and (E)-3-(3,5-di-tert-butyl-4-hydroxyphenyl)acrylic acid with lorazepam were synthesised by a straightforward method at satisfactory to high yields (40%–93%). All the tested derivatives strongly decreased lipidemic indices in rat plasma after Triton induced hyperlipidaemia. They also reduced acute inflammation and a number of them demonstrated lipoxygenase inhibitory activity. Those compounds acquiring antioxidant moiety were inhibitors of lipid peroxidation and radical scavengers. Therefore, the synthesised compounds may add to the current knowledge about multifunctional agents acting against various disorders implicating inflammation, dyslipidaemia and oxidative stress. Full article
Show Figures

Graphical abstract

19 pages, 8407 KiB  
Article
Cathepsin L Inhibitors with Activity against the Liver Fluke Identified From a Focus Library of Quinoxaline 1,4-di-N-Oxide Derivatives
by Florencia Ferraro, Alicia Merlino, Jorge Gil, Hugo Cerecetto, Ileana Corvo and Mauricio Cabrera
Molecules 2019, 24(13), 2348; https://doi.org/10.3390/molecules24132348 - 26 Jun 2019
Cited by 7 | Viewed by 2894
Abstract
Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug [...] Read more.
Infections caused by Fasciola species are widely distributed in cattle and sheep causing significant economic losses, and are emerging as human zoonosis with increasing reports of human cases, especially in children in endemic areas. The current treatment is chemotherapeutic, triclabendazole being the drug of preference since it is active against all parasite stages. Due to the emergence of resistance in several countries, the discovery of new chemical entities with fasciolicidal activity is urgently needed. In our continuous search for new fasciolicide compounds, we identified and characterized six quinoxaline 1,4-di-N-oxide derivatives from our in-house library. We selected them from a screening of novel inhibitors against FhCL1 and FhCL3 proteases, two essential enzymes secreted by juvenile and adult flukes. We report compounds C7, C17, C18, C19, C23, and C24 with an IC50 of less than 10 µM in at least one cathepsin. We studied their binding kinetics in vitro and their enzyme-ligand interactions in silico by molecular docking and molecular dynamic (MD) simulations. These compounds readily kill newly excysted juveniles in vitro and have low cytotoxicity in a Hep-G2 cell line and bovine spermatozoa. Our findings are valuable for the development of new chemotherapeutic approaches against fascioliasis, and other pathologies involving cysteine proteases. Full article
Show Figures

Figure 1

16 pages, 4556 KiB  
Article
In Vitro and In Silico Evaluation of Bikaverin as a Potent Inhibitor of Human Protein Kinase CK2
by Samer Haidar, Dagmar Aichele, Robin Birus, Janine Hielscher, Tuomo Laitinen, Antti Poso and Joachim Jose
Molecules 2019, 24(7), 1380; https://doi.org/10.3390/molecules24071380 - 08 Apr 2019
Cited by 17 | Viewed by 3318
Abstract
Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural [...] Read more.
Protein kinase CK2 is an emerging target for therapeutic intervention in human diseases, particularly in cancer. Inhibitors of this enzyme are currently in clinical trials, indicating the druggability of human CK2. By virtual screening of the ZINC database, we found that the natural compound bikaverin can fit well in the ATP binding site of the target enzyme CK2. By further in vitro evaluation using CK2 holoenzyme, bikaverin turned to be a potent inhibitor with an IC50 value of 1.24 µM. In this work, the cell permeability of bikaverin was determined using a Caco-2 cell permeability assay as a prerequisite for cellular evaluation and the compound turned out to be cell permeable with a Papp- value of 4.46 × 10−6 cm/s. Bikaverin was tested for its effect on cell viability using a MTT assay and cell proliferation using an EdU assay in different cancer cell lines (MCF7, A427 and A431 cells). Cell viability and cell proliferation were reduced dramatically after treatment with 10 µM bikaverin for 24 h. Additionally the IncuCyte® live-cell imaging system was applied for monitoring the cytotoxicity of bikaverin in the three tested cancer cell lines. Finally, molecular dynamic studies were performed to clarify the ligand binding mode of bikaverin at the ATP binding site of CK2 and to identify the amino acids involved. Full article
Show Figures

Graphical abstract

Review

Jump to: Editorial, Research

27 pages, 4316 KiB  
Review
Privileged Scaffolds for Potent and Specific Inhibitors of Mono-ADP-Ribosylating PARPs
by Maria Giulia Nizi, Chiara Sarnari and Oriana Tabarrini
Molecules 2023, 28(15), 5849; https://doi.org/10.3390/molecules28155849 - 03 Aug 2023
Cited by 2 | Viewed by 1318
Abstract
The identification of new targets to address unmet medical needs, better in a personalized way, is an urgent necessity. The introduction of PARP1 inhibitors into therapy, almost ten years ago, has represented a step forward this need being an innovate cancer treatment through [...] Read more.
The identification of new targets to address unmet medical needs, better in a personalized way, is an urgent necessity. The introduction of PARP1 inhibitors into therapy, almost ten years ago, has represented a step forward this need being an innovate cancer treatment through a precision medicine approach. The PARP family consists of 17 members of which PARP1 that works by poly-ADP ribosylating the substrate is the sole enzyme so far exploited as therapeutic target. Most of the other members are mono-ADP-ribosylating (mono-ARTs) enzymes, and recent studies have deciphered their pathophysiological roles which appear to be very extensive with various potential therapeutic applications. In parallel, a handful of mono-ARTs inhibitors emerged that have been collected in a perspective on 2022. After that, additional very interesting compounds were identified highlighting the hot-topic nature of this research field and prompting an update. From the present review, where we have reported only mono-ARTs inhibitors endowed with the appropriate profile of pharmacological tools or drug candidate, four privileged scaffolds clearly stood out that constitute the basis for further drug discovery campaigns. Full article
Show Figures

Figure 1

15 pages, 2782 KiB  
Review
Multiple Strategies to Develop Small Molecular KRAS Directly Bound Inhibitors
by Xile Zhou, Yang Ji and Jinming Zhou
Molecules 2023, 28(8), 3615; https://doi.org/10.3390/molecules28083615 - 21 Apr 2023
Cited by 2 | Viewed by 4251
Abstract
KRAS gene mutation is widespread in tumors and plays an important role in various malignancies. Targeting KRAS mutations is regarded as the “holy grail” of targeted cancer therapies. Recently, multiple strategies, including covalent binding strategy, targeted protein degradation strategy, targeting protein and protein [...] Read more.
KRAS gene mutation is widespread in tumors and plays an important role in various malignancies. Targeting KRAS mutations is regarded as the “holy grail” of targeted cancer therapies. Recently, multiple strategies, including covalent binding strategy, targeted protein degradation strategy, targeting protein and protein interaction strategy, salt bridge strategy, and multivalent strategy, have been adopted to develop KRAS direct inhibitors for anti-cancer therapy. Various KRAS-directed inhibitors have been developed, including the FDA-approved drugs sotorasib and adagrasib, KRAS-G12D inhibitor MRTX1133, and KRAS-G12V inhibitor JAB-23000, etc. The different strategies greatly promote the development of KRAS inhibitors. Herein, the strategies are summarized, which would shed light on the drug discovery for both KRAS and other “undruggable” targets. Full article
Show Figures

Figure 1

39 pages, 9013 KiB  
Review
Medicinal Chemistry of Anti-HIV-1 Latency Chemotherapeutics: Biotargets, Binding Modes and Structure-Activity Relationship Investigation
by Yan-Kai Wang, Long Wei, Wei Hu, Pei-Xia Yu, Zhong Li, Hai-Peng Yu and Xun Li
Molecules 2023, 28(1), 3; https://doi.org/10.3390/molecules28010003 - 20 Dec 2022
Cited by 2 | Viewed by 1935
Abstract
The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to [...] Read more.
The existence of latent viral reservoirs (LVRs), also called latent cells, has long been an acknowledged stubborn hurdle for effective treatment of HIV-1/AIDS. This stable and heterogeneous reservoir, which mainly exists in resting memory CD4+ T cells, is not only resistant to highly active antiretroviral therapy (HAART) but cannot be detected by the immune system, leading to rapid drug resistance and viral rebound once antiviral treatment is interrupted. Accordingly, various functional cure strategies have been proposed to combat this barrier, among which one of the widely accepted and utilized protocols is the so-called ‘shock-and-kill’ regimen. The protocol begins with latency-reversing agents (LRAs), either alone or in combination, to reactivate the latent HIV-1 proviruses, then eliminates them by viral cytopathic mechanisms (e.g., currently available antiviral drugs) or by the immune killing function of the immune system (e.g., NK and CD8+ T cells). In this review, we focuse on the currently explored small molecular LRAs, with emphasis on their mechanism-directed drug targets, binding modes and structure-relationship activity (SAR) profiles, aiming to provide safer and more effective remedies for treating HIV-1 infection. Full article
Show Figures

Figure 1

39 pages, 5772 KiB  
Review
Research Progress on Small Molecular Inhibitors of the Type 3 Secretion System
by Chao Lv, Ying Li, Yuxia Wei, Jiayu Wang, Hui Yu, Feng Gao, Chao Zhu, Xiangdi Jia, Mingqiong Tong, Pingxuan Dong, Qianqian Gao and Longlong Geng
Molecules 2022, 27(23), 8348; https://doi.org/10.3390/molecules27238348 - 30 Nov 2022
Cited by 1 | Viewed by 2431
Abstract
The overuse of antibiotics has led to severe bacterial drug resistance. Blocking pathogen virulence devices is a highly effective approach to combating bacterial resistance worldwide. Type three secretion systems (T3SSs) are significant virulence factors in Gram-negative pathogens. Inhibition of these systems can effectively [...] Read more.
The overuse of antibiotics has led to severe bacterial drug resistance. Blocking pathogen virulence devices is a highly effective approach to combating bacterial resistance worldwide. Type three secretion systems (T3SSs) are significant virulence factors in Gram-negative pathogens. Inhibition of these systems can effectively weaken infection whilst having no significant effect on bacterial growth. Therefore, T3SS inhibitors may be a powerful weapon against resistance in Gram-negative bacteria, and there has been increasing interest in the research and development of T3SS inhibitors. This review outlines several reported small-molecule inhibitors of the T3SS, covering those of synthetic and natural origin, including their sources, structures, and mechanisms of action. Full article
Show Figures

Figure 1

18 pages, 4138 KiB  
Review
Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development
by Fangjiao Huang, Xiaoli Han, Xiaohui Xiao and Jinming Zhou
Molecules 2022, 27(22), 7728; https://doi.org/10.3390/molecules27227728 - 10 Nov 2022
Cited by 17 | Viewed by 9587
Abstract
Cysteine is one of the least abundant amino acids in proteins of many organisms, which plays a crucial role in catalysis, signal transduction, and redox regulation of gene expression. The thiol group of cysteine possesses the ability to perform nucleophilic and redox-active functions [...] Read more.
Cysteine is one of the least abundant amino acids in proteins of many organisms, which plays a crucial role in catalysis, signal transduction, and redox regulation of gene expression. The thiol group of cysteine possesses the ability to perform nucleophilic and redox-active functions that are not feasible for other natural amino acids. Cysteine is the most common covalent amino acid residue and has been shown to react with a variety of warheads, especially Michael receptors. These unique properties have led to widespread interest in this nucleophile, leading to the development of a variety of cysteine-targeting warheads with different chemical compositions. Herein, we summarized the various covalent warheads targeting cysteine residue and their application in drug development. Full article
Show Figures

Figure 1

28 pages, 5609 KiB  
Review
Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates
by Adriana Coricello, Francesco Mesiti, Antonio Lupia, Annalisa Maruca and Stefano Alcaro
Molecules 2020, 25(15), 3321; https://doi.org/10.3390/molecules25153321 - 22 Jul 2020
Cited by 20 | Viewed by 5829
Abstract
The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application [...] Read more.
The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up. Full article
Show Figures

Figure 1

15 pages, 1652 KiB  
Review
The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i
by Giuseppe Cianciolo, Antonio De Pascalis, Lorenzo Gasperoni, Francesco Tondolo, Fulvia Zappulo, Irene Capelli, Maria Cappuccilli and Gaetano La Manna
Molecules 2020, 25(12), 2757; https://doi.org/10.3390/molecules25122757 - 15 Jun 2020
Cited by 15 | Viewed by 6163
Abstract
The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site [...] Read more.
The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis. Full article
Show Figures

Figure 1

Back to TopTop