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Enzyme Inhibitors: Discovery, Synthesis and Medical Applications

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 9037

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Special Issue Editors

Dr. Elisa Nuti

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Guest Editor

Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
Interests: medicinal chemistry; metallo-enzyme inhibitors; drug discovery; synthesis of biologically active compounds; fluorescent probes
Special Issues, Collections and Topics in MDPI journals

Dr. Doretta Cuffaro

E-Mail Website
Guest Editor

1. Department of Pharmacy, University of Pisa, 56126 Pisa, Italy
2. Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56100 Pisa, Italy
Interests: phytochemicals; polyphenols; nutraceuticals; bioactives; food waiste; olive oil; medicinal chemistry; synthetic chemistry; analytical chemistry; biological screening
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Enzymes represent a medicinal chemistry target largely investigated in recent decades. Since they are involved in the regulation of a wide range of physiological processes, dysfunctional, over-expressed, or over-reactive enzymes are significantly responsible for the development of pathological conditions such as cancer, inflammation, diabetes, microbial and viral infections. Kinases, proteases, phosphatases, and peptidases are the most common targets of newly developed drugs. Recent studies involving the resolution of enzyme crystal structures, site directed mutagenesis of catalytic residues and molecular modeling of catalytic domains have opened the way to the synthesis of more effective and selective agents.

We would like to invite authors to contribute to this Special Issue with original research and review articles focused on the most recent advances in the development of inhibitors of enzymes such as carbonic anhydrases, zinc-metalloproteinases, histone deacetylases (HDACs), angiotensin-converting enzyme (ACE), cyclooxygenase-1/cyclooxygenase-2 (COX-1/COX-2), HIV-1 integrase, aldose reductase, the Main Protease of SARS-CoV-2 (Mpro) among others. Original papers could report not only the design and synthesis of synthetic or natural-derived enzyme inhibitors but also their biological evaluation and pharmacokinetics.

Dr. Elisa Nuti
Dr. Doretta Cuffaro
Guest Editors

Manuscript Submission Information

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Keywords

drug design
synthesis
structure-activity relationships
covalent enzyme inhibitors
reversible enzyme inhibitors
irreversible enzyme inhibitors
allosteric enzyme inhibitors

Published Papers (5 papers)

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Research

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17 pages, 8183 KiB

Open AccessArticle

Novel 7-Deazapurine Incorporating Isatin Hybrid Compounds as Protein Kinase Inhibitors: Design, Synthesis, In Silico Studies, and Antiproliferative Evaluation

by Mohammed M. Alanazi and Ashwag S. Alanazi

Molecules 2023, 28(15), 5869; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28155869 - 04 Aug 2023

Cited by 4 | Viewed by 1115

Abstract

Cancer is a multifactorial disorder with extremely complex genetics and progression. The major challenge in cancer therapy is the development of cancer resistance and relapse. Conventional anticancer drugs directly target the DNA of the cell, while modern chemotherapeutic drugs include molecular-targeted therapy, such as targeting the abnormal cell signaling inside the cancer cells. Targeted chemotherapy is effective in several malignancies; however, the success has always been limited by drug resistance and/or side effects. Anticancer with multi-targeted actions simultaneously modulates multiple cancer cell signaling pathways and, therefore, may ease the chance of effective anticancer drug development. In this research, a series of 7-deazapurine incorporating isatin hybrid compounds was designed and successfully synthesized. Among those hybrids, compound 5 demonstrated a very potent cytotoxic effect compared to the reference anticancer drug against four cancer cell lines. Likewise, compound 5 inhibited the activity of four protein kinase enzymes in nanomolar ranges. Further analysis of the biological evaluation of compound 5 revealed the capability of compound 5 to arrest cell cycle progression and induce programmed cell death. Moreover, molecular simulation studies were performed to investigate the possible types of interactions between compound 5 and the investigated protein kinases. Finally, taking into consideration all the abovementioned findings, compound 5 could be a good candidate for further investigations. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Discovery, Synthesis and Medical Applications)

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24 pages, 8902 KiB

Open AccessArticle

Structural and Mechanistic Basis for the Inactivation of Human Ornithine Aminotransferase by (3S,4S)-3-Amino-4-fluorocyclopentenecarboxylic Acid

by Sida Shen, Arseniy Butrin, Brett A. Beaupre, Glaucio M. Ferreira, Peter F. Doubleday, Daniel H. Grass, Wei Zhu, Neil L. Kelleher, Graham R. Moran, Dali Liu and Richard B. Silverman

Molecules 2023, 28(3), 1133; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031133 - 23 Jan 2023

Cited by 1 | Viewed by 1949

Abstract

Ornithine aminotransferase (OAT) is overexpressed in hepatocellular carcinoma (HCC), and we previously showed that inactivation of OAT inhibits the growth of HCC. Recently, we found that (3S,4S)-3-amino-4-fluorocyclopentenecarboxylic acid (5) was a potent inactivator of γ-aminobutyric acid aminotransferase (GABA-AT), proceeding by an enamine mechanism. Here we describe our investigations into the activity and mechanism of 5 as an inactivator of human OAT. We have found that 5 exhibits 10-fold less inactivation efficiency (k_inact/K_I) against hOAT than GABA-AT. A comprehensive mechanistic study was carried out to understand its inactivation mechanism with hOAT. pK_a and electrostatic potential calculations were performed to further support the notion that the α,β-unsaturated alkene of 5 is critical for enhancing acidity and nucleophilicity of the corresponding intermediates and ultimately responsible for the improved inactivation efficiency of 5 over the corresponding saturated analogue (4). Intact protein mass spectrometry and the crystal structure complex with hOAT provide evidence to conclude that 5 mainly inactivates hOAT through noncovalent interactions, and that, unlike with GABA-AT, covalent binding with hOAT is a minor component of the total inhibition which is unique relative to other monofluoro-substituted derivatives. Furthermore, based on the results of transient-state measurements and free energy calculations, it is suggested that the α,β-unsaturated carboxylate group of PLP-bound 5 may be directly involved in the inactivation cascade by forming an enolate intermediate. Overall, compound 5 exhibits unusual structural conversions which are catalyzed by specific residues within hOAT, ultimately leading to an enamine mechanism-based inactivation of hOAT through noncovalent interactions and covalent modification. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Discovery, Synthesis and Medical Applications)

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24 pages, 9149 KiB

Open AccessArticle

Interactions of Apigenin and Safranal with the 5HT1A and 5HT2A Receptors and Behavioral Effects in Depression and Anxiety: A Molecular Docking, Lipid-Mediated Molecular Dynamics, and In Vivo Analysis

by Faiq Amin, Mahmoud A. A. Ibrahim, Syed Rizwan-ul-Hasan, Saima Khaliq, Gamal A. Gabr, Muhammad, Asra Khan, Peter A. Sidhom, Prashant Tikmani, Ahmed M. Shawky, Saara Ahmad and Syed Hani Abidi

Molecules 2022, 27(24), 8658; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27248658 - 07 Dec 2022

Cited by 6 | Viewed by 2271

Abstract

Background: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. Methods: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. Results: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. Conclusions: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Discovery, Synthesis and Medical Applications)

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Review

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30 pages, 12314 KiB

Open AccessReview

Bacterial Zinc Metalloenzyme Inhibitors: Recent Advances and Future Perspectives

by Riccardo Di Leo, Doretta Cuffaro, Armando Rossello and Elisa Nuti

Molecules 2023, 28(11), 4378; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28114378 - 27 May 2023

Cited by 2 | Viewed by 1432

Abstract

Human deaths caused by Gram-negative bacteria keep rising due to the multidrug resistance (MDR) phenomenon. Therefore, it is a priority to develop novel antibiotics with different mechanisms of action. Several bacterial zinc metalloenzymes are becoming attractive targets since they do not show any similarities with the human endogenous zinc-metalloproteinases. In the last decades, there has been an increasing interest from both industry and academia in developing new inhibitors against those enzymes involved in lipid A biosynthesis, and bacteria nutrition and sporulation, e.g., UDP-[3-O-(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), thermolysin (TLN), and pseudolysin (PLN). Nevertheless, targeting these bacterial enzymes is harder than expected and the lack of good clinical candidates suggests that more effort is needed. This review gives an overview of bacterial zinc metalloenzyme inhibitors that have been synthesized so far, highlighting the structural features essential for inhibitory activity and the structure–activity relationships. Our discussion may stimulate and help further studies on bacterial zinc metalloenzyme inhibitors as possible novel antibacterial drugs. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Discovery, Synthesis and Medical Applications)

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15 pages, 1638 KiB

Open AccessReview

Targeting DNA Topoisomerase II in Antifungal Chemotherapy

by Kavya Kondaka and Iwona Gabriel

Molecules 2022, 27(22), 7768; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227768 - 11 Nov 2022

Cited by 3 | Viewed by 1710

Abstract

Topoisomerase inhibitors have been in use clinically for the treatment of several diseases for decades. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoisomerase II (topo II). Raising concern for the fungal infections, lack of effective drugs and a phenomenon of multidrug resistance underlie a strong need to expand the range of therapeutic options. In this review paper, we discussed the usefulness of fungal topo II as a molecular target for new drug discovery. On the basis of previously published data, we described structural and biochemical differences between fungal and human enzymes as well as a molecular basis of differential sensitivity to known anticancer drugs targeting the latter. This review focuses especially on highlighting the differences that may underlie the selectivity of action of new inhibitors. Distinct sites within fungal topo II in comparison with human counterparts are observed and should be further studied to understand the significance of those sites and their possible usage in design of new drugs. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Discovery, Synthesis and Medical Applications)

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