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Special Issue "Trends in the Development of Enzyme Inhibitors"

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

Deadline for manuscript submissions: 31 July 2019

Special Issue Editor

Guest Editor
Prof. Dr. Tiziano Tuccinardi

Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Website | E-Mail
Interests: medicinal chemistry; drug design; ligand-protein binding, molecular interactions; molecular modeling; hit identification; lead optimization

Special Issue Information

Dear Colleagues,

This Special Issue is entitled “Trends in the Development of Enzyme Inhibitors”. The identification of small molecules able to inhibit the activity of specific target enzymes is probably one of the most studied and important research fields in the history of drug discovery. Nevertheless, due to the growing amount of information regarding the role of enzymes in various therapeutic areas, this field is still one of the most studied. Thanks to all the reported studies about new enzyme targets that may represent innovative therapeutic opportunities, and also thanks to the development and optimization of novel technologies, the identification of enzyme inhibitors has become a common goal for medicinal chemists and chemical biologists. This Special Issue aims to provide a forum for the dissemination of: a) the latest information on novel approaches for the identification and optimization of enzyme inhibitors and b) research studies reporting the design, synthesis, and biological evaluation of potentially-active inhibitors.

Prof. Dr. Tiziano Tuccinardi
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 papers will be 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 1800 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

  • medicinal chemistry
  • drug design
  • ligand-protein binding, molecular interactions
  • molecular modeling
  • hit identification
  • lead optimization

Published Papers (6 papers)

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Research

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Open AccessArticle
Design, Synthesis, Docking Studies and Monoamine Oxidase Inhibition of a Small Library of 1-acetyl- and 1-thiocarbamoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazoles
Molecules 2019, 24(3), 484; https://doi.org/10.3390/molecules24030484
Received: 28 December 2018 / Revised: 24 January 2019 / Accepted: 27 January 2019 / Published: 29 January 2019
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Abstract
New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of [...] Read more.
New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of the substituents at N1, C3 and C5 positions as well the influence of the configuration of the C5 on the biological activity were analyzed. Bulky aromatic groups at C5 were not tolerated. p-Prenyloxyaryl moiety at C3 oriented the selectivity toward the B isoform. The results were also corroborated by molecular modelling studies providing new suggestions for the synthesis of privileged structures to serve as lead compounds for the treatment of mood disorders and neurodegenerative diseases. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Open AccessArticle
Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition
Molecules 2019, 24(2), 317; https://doi.org/10.3390/molecules24020317
Received: 24 December 2018 / Revised: 12 January 2019 / Accepted: 13 January 2019 / Published: 16 January 2019
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Abstract
In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The [...] Read more.
In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (18), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. All the compounds (18) showed a significant inhibition to bacterial NA with IC50 values of 0.17–106.3 µM. In particular, the prenyl group on the flavonoids played a critical role in bacterial NA inhibition. Epimedokoreanin B (compound 1, IC50 = 0.17 µM) with two prenyl groups on C8 and C5′ of luteolin was 500 times more effective than luteolin (IC50 = 85.6 µM). A similar trend was observed on compound 2 (IC50 = 0.68 µM) versus dihydrokaempferol (IC50 = 500.4 µM) and compound 3 (IC50 = 12.6 µM) versus apigenin (IC50 = 107.5 µM). Kinetic parameters (Km, Vmax, and Kik/Kiv) evaluated that all the compounds apart from compound 5 showed noncompetitive inhibition. Compound 5 was proven to be a mixed type inhibitor. In an enzyme binding affinity experiment using fluorescence, affinity constants (KSV) were tightly related to inhibitory activities. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Open AccessArticle
Cloning, Characterization and Anion Inhibition Studies of a β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica
Molecules 2018, 23(12), 3112; https://doi.org/10.3390/molecules23123112
Received: 1 November 2018 / Revised: 27 November 2018 / Accepted: 27 November 2018 / Published: 28 November 2018
Cited by 2 | PDF Full-text (1788 KB) | HTML Full-text | XML Full-text
Abstract
We report the cloning and catalytic activity of a β-carbonic anhydrase (CA, EC 4.2.1.1), isolated from the pathogenic protozoan Entamoeba histolytica, EhiCA. This enzyme has a high catalytic activity for the physiologic CO2 hydration reaction, with a kcat of 6.7 [...] Read more.
We report the cloning and catalytic activity of a β-carbonic anhydrase (CA, EC 4.2.1.1), isolated from the pathogenic protozoan Entamoeba histolytica, EhiCA. This enzyme has a high catalytic activity for the physiologic CO2 hydration reaction, with a kcat of 6.7 × 105 s−1 and a kcat/Km of 8.9 × 107 M−1 × s−1. An anion inhibition study of EhiCA with inorganic/organic anions and small molecules revealed that fluoride, chloride, cyanide, azide, pyrodiphosphate, perchlorate, tetrafluoroborate and sulfamic acid did not inhibit the enzyme activity, whereas pseudohalides (cyanate and thiocyanate), bicarbonate, nitrate, nitrite, diethyldithiocarbamate, and many complex inorganic anions showed inhibition in the millimolar range (KIs of 0.51–8.4 mM). The best EhiCA inhibitors were fluorosulfonate, sulfamide, phenylboronic acid and phenylarsonic acid (KIs in the range of 28–86 μM). Since β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of effective enzyme inhibitors, with potential to develop anti-infectives with alternative mechanisms of action. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Open AccessArticle
Screening of Angiotensin-I Converting Enzyme Inhibitory Peptides Derived from Caulerpa lentillifera
Molecules 2018, 23(11), 3005; https://doi.org/10.3390/molecules23113005
Received: 14 October 2018 / Revised: 11 November 2018 / Accepted: 15 November 2018 / Published: 16 November 2018
Cited by 1 | PDF Full-text (4741 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera [...] Read more.
Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera (known commonly as sea grape) protein hydrolysate. In this study, short-chain peptides were obtained after hydrolysis by various enzymes and subsequently by ultrafiltration. Thermolysin hydrolysate showed the highest ACEI activity. Bioassay-guided fractionation was performed using reversed-phase high performance liquid chromatography (RP-HPLC) to uncover the fraction 9 with the highest ACE inhibitory activity from thermolysin hydrolysate. Peptides in this fraction were further identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis coupled with de novo sequencing, which gave two oligopeptides, FDGIP (FP-5) and AIDPVRA (AA-7). The identities and activities of these two peptides were further confirmed using synthetic peptides. Their IC50 values were determined as 58.89 ± 0.68 µM and 65.76 ± 0.92 µM, respectively. Moreover, the inhibition kinetics revealed that both FP-5 and AA-7 are competitive inhibitors. These activities were further explained using molecular docking simulation. The present study is the first report about ACEI peptides derived from Caulerpa lentillifera and it shows the potential for preventing hypertension and for functional food development. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Open AccessArticle
Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors
Molecules 2018, 23(9), 2369; https://doi.org/10.3390/molecules23092369
Received: 12 July 2018 / Revised: 12 September 2018 / Accepted: 13 September 2018 / Published: 17 September 2018
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Abstract
Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. [...] Read more.
Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC50s in the nanomolar range, with 2–130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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Review

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Open AccessReview
Pharmacological Inhibition of LSD1 for Cancer Treatment
Molecules 2018, 23(12), 3194; https://doi.org/10.3390/molecules23123194
Received: 15 November 2018 / Revised: 30 November 2018 / Accepted: 30 November 2018 / Published: 4 December 2018
Cited by 3 | PDF Full-text (2676 KB) | HTML Full-text | XML Full-text
Abstract
Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is [...] Read more.
Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. Pharmacological inhibition of LSD1 has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of LSD1, its role in carcinogenesis, a comparison of currently available approaches for screening LSD1 inhibitors, a classification of LSD1 inhibitors, and its potential as a drug target in cancer therapy. Full article
(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)
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