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Molecules
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Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds
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Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 14051

Special Issue Editors

Dr. Sophia S. Borisevich

E-Mail Website
Guest Editor
Ufa Institute of Chemistry, Ufa Federal Research Center Russian Academy of Science, 450054 Ufa, Russia
Interests: Molecular modeling; quantum chemical calculations; molecular docking and dynamics; surface fusion type 1 proteins: hemagglutinin, spike-protein, and F-protein
Prof. Dr. Vladimir V. Zarubaev

E-Mail Website
Guest Editor
Saint Petersburg Pasteur Research Institute of Epidemiology and Microbiology, 197101 Saint Petersburg, Russia
Interests: viruses; antiviral agents; antiviral activity; medicinal chemistry; virus replication; virus disease; viral drug resistance
Prof. Dr. Olga Yarovaya

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: medicinal chemistry; chemistry of natural compounds; terpenes; virology; analytical chemistry in preclinical research; natural product chemistry; synthesis of heterocycles
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue of the journal Molecules is dedicated to the development and synthesis of new biologically active compounds.

Obviously, the creation of fundamentally new drugs is impossible without the use of molecular modelling methods. The search for evidence of a therapeutic target, estimations of the affinity of active compounds to a potential binding site, and the structural modification of biologically active compounds require an in silico approach.

 Molecular modelling (docking or molecular dynamic simulations) and quantum chemical calculations are powerful tools that, with the right approach, can greatly facilitate the task of drug design. Moreover, successful attempts to apply molecular modelling methods have taken place. High-throughput in silico screening is cheaper than large-scale biological experiments. However, it is impossible to achieve successful results in theoretical experiments without the use of aggregate experimental data. Articles devoted to the development of new drugs, including molecular modelling methods in combination with data from biological experiments, are welcome in particular.

Dr. Sophia S. Borisevich
Prof. Dr. Vladimir V. Zarubaev
Prof. Dr. Olga Yarovaya
Guest Editors

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

  • molecular modelling
  • structure-based drug design
  • small molecule drugs
  • structure-activity relationships
  • synthesis of biologically active compounds
  • drug discovery
  • in silico screening

Published Papers (7 papers)

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Research

19 pages, 2564 KiB  
Article
Synthesis and Assessment of Antiplatelet and Antithrombotic Activity of 4-Amino-Substituted 5-Oxoproline Amides and Peptides
by Victor P. Krasnov, Irina A. Nizova, Alexey Yu. Vigorov, Tatyana V. Matveeva, Galina L. Levit, Mikhail I. Kodess, Marina A. Ezhikova, Pavel A. Slepukhin, Dmitry A. Bakulin, Ivan N. Tyurenkov and Valery N. Charushin
Molecules 2023, 28(21), 7401; https://doi.org/10.3390/molecules28217401 - 2 Nov 2023
Viewed by 968
Abstract
Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for [...] Read more.
Venous thromboembolism is a serious problem because it significantly increases the risk of developing vascular complications in elderly patients with obesity or immobilization, cancer, and many other diseases. Thus, there is a need to study new therapeutic strategies, including new medicinal agents for the efficient and safe correction of thrombus disorders. In this work, we have synthesized a number of new amides and peptides of 4-amino-5-oxoprolines and studied their antiplatelet and antithrombotic activity in experiments in vitro and in vivo. It has been found that the newly obtained compounds slow down the process of thrombus formation in a model of arterial and venous thrombosis, without affecting plasma hemostasis parameters. (2S,4S)-4-Amino-1-(4-fluorophenyl)-5-oxoprolyl-(S)-phenylalanine proved to be the most efficient among the studied derivatives. The results obtained indicate the advisability of further studies on 5-oxoproline derivatives in order to design pharmaceutical agents for the prevention and treatment of the consequences of thrombosis. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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22 pages, 6420 KiB  
Article
Large Subunit of the Human Herpes Simplex Virus Terminase as a Promising Target in Design of Anti-Herpesvirus Agents
by Victor P. Krasnov, Valeriya L. Andronova, Alexander V. Belyavsky, Sophia S. Borisevich, George A. Galegov, Oleg F. Kandarakov, Dmitry A. Gruzdev, Olga A. Vozdvizhenskaya and Galina L. Levit
Molecules 2023, 28(21), 7375; https://doi.org/10.3390/molecules28217375 - 31 Oct 2023
Viewed by 1893
Abstract
Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral [...] Read more.
Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral drugs used to treat HSV infections, acyclovir and related compounds, as well as foscarnet and cidofovir, selectively inhibit herpesvirus DNA polymerase (DNA-pol). It has been previously found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (compound 1) exhibits selective anti-herpesvirus activity against HSV-1 in cell culture, including acyclovir-resistant mutants, so we consider it as a lead compound. In this work, the selection of HSV-1 clones resistant to the lead compound was carried out. High-throughput sequencing of resistant clones and reference HSV-1/L2 parent strain was performed to identify the genetic determinants of the virus’s resistance to the lead compound. We identified a candidate mutation presumably associated with resistance to the virus, namely the T321I mutation in the UL15 gene encoding the large terminase subunit. Molecular modeling was used to evaluate the affinity and dynamics of the lead compound binding to the putative terminase binding site. The results obtained suggest that the lead compound, by binding to pUL15, affects the terminase complex. pUL15, which is directly involved in the processing and packaging of viral DNA, is one of the crucial components of the HSV terminase complex. The loss of its functional activity leads to disruption of the formation of mature virions, so it represents a promising drug target. The discovery of anti-herpesvirus agents that affect biotargets other than DNA polymerase will expand our possibilities of targeting HSV infections, including those resistant to baseline drugs. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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37 pages, 24390 KiB  
Article
Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders
by Dishary Sharmin, Md Yeunus Mian, Michael Marcotte, Thomas D. Prevot, Etienne Sibille, Jeffrey M. Witkin and James M. Cook
Molecules 2023, 28(12), 4771; https://doi.org/10.3390/molecules28124771 - 14 Jun 2023
Cited by 1 | Viewed by 2415
Abstract
GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 [...] Read more.
GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer’s disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their Ki values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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18 pages, 2442 KiB  
Article
Gut Protective Effect from D-Methionine or Butyric Acid against DSS and Carrageenan-Induced Ulcerative Colitis
by Yuka Ikeda and Satoru Matsuda
Molecules 2023, 28(11), 4392; https://doi.org/10.3390/molecules28114392 - 28 May 2023
Cited by 3 | Viewed by 2482
Abstract
Microbiome dysbiosis resulting in altered metabolite profiles may be associated with certain diseases, including inflammatory bowel diseases (IBD), which are characterized by active intestinal inflammation. Several studies have indicated the beneficial anti-inflammatory effect of metabolites from gut microbiota, such as short-chain fatty acids [...] Read more.
Microbiome dysbiosis resulting in altered metabolite profiles may be associated with certain diseases, including inflammatory bowel diseases (IBD), which are characterized by active intestinal inflammation. Several studies have indicated the beneficial anti-inflammatory effect of metabolites from gut microbiota, such as short-chain fatty acids (SCFAs) and/or D-amino acids in IBD therapy, through orally administered dietary supplements. In the present study, the potential gut protective effects of d-methionine (D-Met) and/or butyric acid (BA) have been investigated in an IBD mouse model. We have also built an IBD mouse model, which was cost-effectively induced with low molecular weight DSS and kappa-carrageenan. Our findings revealed that D-Met and/or BA supplementation resulted in the attenuation of the disease condition as well as the suppression of several inflammation-related gene expressions in the IBD mouse model. The data shown here may suggest a promising therapeutic potential for improving symptoms of gut inflammation with an impact on IBD therapy. However, molecular metabolisms need to be further explored. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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19 pages, 3591 KiB  
Article
Development of Combretastatin A-4 Analogues as Potential Anticancer Agents with Improved Aqueous Solubility
by Zhi-Hao Chen, Run-Mei Xu, Guang-Hao Zheng, Ye-Zhi Jin, Yuan Li, Xin-Yuan Chen and Yu-Shun Tian
Molecules 2023, 28(4), 1717; https://doi.org/10.3390/molecules28041717 - 10 Feb 2023
Cited by 9 | Viewed by 1665
Abstract
Combretastatin A-4 (CA-4) is a potent tubulin polymerisation inhibitor. However, the clinical application of CA-4 is limited owing to its low aqueous solubility and the easy conversion of the olefin double bond from the more active cis- to the less active trans-configuration. [...] Read more.
Combretastatin A-4 (CA-4) is a potent tubulin polymerisation inhibitor. However, the clinical application of CA-4 is limited owing to its low aqueous solubility and the easy conversion of the olefin double bond from the more active cis- to the less active trans-configuration. Several structural modifications were investigated to improve the solubility of CA-4 derivatives. Among the compounds we synthesized, the kinetic solubility assay revealed that the solubility of compounds containing a piperazine ring increased the most, and the solubility of compounds 12a1, 12a2, 15 and 18 was increased 230–2494 times compared with that of the control compound (Z)-3-(4-aminophenyl)-2-(3,4,5-trimethoxyphenyl)acrylonitrile (9a). In addition, these synthesised stilbene nitriles had high anticancer cell (AGS, BEL-7402, MCF-7, and HCT-116) selectivity over L-02 and MCF-10A normal cells while maintaining micromolar activity against cancer cells. The most cytotoxic compound is 9a, and the IC50 value is 20 nM against HCT-116 cancer cells. Preliminary studies indicated that compound 12a1 had excellent plasma stability and moderate binding to rat plasma proteins, suggesting it is a promising lead compound for the development of an anticancer agent. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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27 pages, 5189 KiB  
Article
Design, Synthesis and Biological Evaluation of Conjugates of 3-O-Descladinose-azithromycin and Nucleobases against rRNA A2058G- or A2059G-Mutated Strains
by Xiaotian Lian, Wentian Liu, Bingzhi Fan, Mingjia Yu and Jianhua Liang
Molecules 2023, 28(3), 1327; https://doi.org/10.3390/molecules28031327 - 30 Jan 2023
Viewed by 1564
Abstract
Structurally unrelated antibiotics MLSB (macrolide-lincosamide-streptogramin B) compromised with clinically resistant pathogens because of the cross-resistance resulting from the structural modification of rRNA A2058. The structure–activity relationships of a novel 3-O-descladinose azithromycin chemotype conjugating with nucleobases were fully explored with the [...] Read more.
Structurally unrelated antibiotics MLSB (macrolide-lincosamide-streptogramin B) compromised with clinically resistant pathogens because of the cross-resistance resulting from the structural modification of rRNA A2058. The structure–activity relationships of a novel 3-O-descladinose azithromycin chemotype conjugating with nucleobases were fully explored with the aid of engineered E. coli SQ110DTC and SQ110LPTD. The conjugates of macrolides with nucleobases, especially adenine, displayed antibacterial superiority over telithromycin, azithromycin and clindamycin against rRNA A2058/2059-mutated engineered E. coli strains at the cost of lowering permeability and increasing vulnerability to efflux proteins against clinical isolates. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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14 pages, 7279 KiB  
Article
Triterpenic Acid Amides as Potential Inhibitors of the SARS-CoV-2 Main Protease
by Dmitry S. Baev, Mikhail E. Blokhin, Varvara Yu. Chirkova, Svetlana V. Belenkaya, Olga A. Luzina, Olga I. Yarovaya, Nariman F. Salakhutdinov and Dmitry N. Shcherbakov
Molecules 2023, 28(1), 303; https://doi.org/10.3390/molecules28010303 - 30 Dec 2022
Cited by 6 | Viewed by 1777
Abstract
Although the incidence and mortality of SARS-CoV-2 infection has been declining during the pandemic, the problem related to designing novel antiviral drugs that could effectively resist viruses in the future remains relevant. As part of our continued search for chemical compounds that are [...] Read more.
Although the incidence and mortality of SARS-CoV-2 infection has been declining during the pandemic, the problem related to designing novel antiviral drugs that could effectively resist viruses in the future remains relevant. As part of our continued search for chemical compounds that are capable of exerting an antiviral effect against the SARS-CoV-2 virus, we studied the ability of triterpenic acid amides to inhibit the SARS-CoV-2 main protease. Molecular modeling suggested that the compounds are able to bind to the active site of the main protease via non-covalent interactions. The FRET-based enzyme assay was used to reveal that compounds 1e and 1b can inhibit the SARS-CoV-2 main protease at micromolar concentrations. Full article
(This article belongs to the Special Issue Synthesis, Biological Evaluation and Molecular Modeling of Bioactive Compounds)
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