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Viruses
Special Issues
Viral Enzyme Inhibitors: Structure and Dynamics
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Viral Enzyme Inhibitors: Structure and Dynamics

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 6583

Special Issue Editor

Dr. Krishan K. Pandey

E-Mail Website
Guest Editor
School of Medicine, Saint Louis University, Saint Louis, MO 63103, USA
Interests: retrovirus; HIV-1; Rous sarcoma virus; integration

Special Issue Information

Dear Colleagues,

Viruses need the host cellular machinery to reproduce, though most viruses have at least one enzyme encoded in their genome for replication or other essential function. Targeting viral enzymes to inhibit their replication has been an attractive approach and proven to be successful in several instances. Some of these enzymes include DNA and RNA polymerases, reverse transcriptase required for viral genome replication, proteases for the processing of viral proteins and other essential viral enzymes performing specific functions. Generally, it is easier to target viral enzymes to develop inhibitors as they might have differences from analogous cellular enzymes and proteins, though this is not always the case. Advances in structural biology technologies have accelerated the determination of structures of otherwise refractory viral proteins, either alone or complexed with their cognate substrates. The availability of higher-resolution structures facilitates the development of novel and next-generation inhibitors against essential viral enzymes.

This Special Issue will cover recent developments about the biology of several essential viral enzymes, their structure and functions, inhibition, development of drug resistance and the need for the continual development of new inhibitors.

Dr. Krishan K. Pandey
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. Viruses is an international peer-reviewed open access monthly 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 2600 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

  • viral enzymes
  • antiviral drugs
  • drug development
  • drug resistance
  • rational drug design

Published Papers (3 papers)

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Research

14 pages, 2528 KiB  
Article
Quinazolinone-Peptido-Nitrophenyl-Derivatives as Potential Inhibitors of SARS-CoV-2 Main Protease
by Huynh-Nguyet-Huong Giang, Feng-Pai Chou, Ching-Yun Chen, Shen-Chieh Chou, Sheng-Cih Huang, Tuoh Wu, Bui-Thi-Buu Hue, Hong-Cheu Lin and Tung-Kung Wu
Viruses 2023, 15(2), 287; https://doi.org/10.3390/v15020287 - 19 Jan 2023
Cited by 1 | Viewed by 1701
Abstract
The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-Mpro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the [...] Read more.
The severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2-Mpro) plays an essential role in viral replication, transcription, maturation, and entry into host cells. Furthermore, its cleavage specificity for viruses, but not humans, makes it a promising drug target for the treatment of coronavirus disease 2019 (COVID-19). In this study, a fragment-based strategy including potential antiviral quinazolinone moiety and glutamine- or glutamate-derived peptidomimetic backbone and positioned nitro functional groups was used to synthesize putative Mpro inhibitors. Two compounds, G1 and G4, exhibited anti-Mpro enzymatic activity in a dose-dependent manner, with the calculated IC50 values of 22.47 ± 8.93 μM and 24.04 ± 0.67 μM, respectively. The bio-layer interferometer measured real-time binding. The dissociation kinetics of G1/Mpro and G4/Mpro also showed similar equilibrium dissociation constants (KD) of 2.60 × 10−5 M and 2.55 × 10−5 M, respectively, but exhibited distinct association/dissociation curves. Molecular docking of the two compounds revealed a similar binding cavity to the well-known Mpro inhibitor GC376, supporting a structure−function relationship. These findings may open a new avenue for developing new scaffolds for Mpro inhibition and advance anti-coronavirus drug research. Full article
(This article belongs to the Special Issue Viral Enzyme Inhibitors: Structure and Dynamics)
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23 pages, 8849 KiB  
Article
Chetomin, a SARS-CoV-2 3C-like Protease (3CLpro) Inhibitor: In Silico Screening, Enzyme Docking, Molecular Dynamics and Pharmacokinetics Analysis
by Mahmoud A. A. Ibrahim, Alaa H. M. Abdelrahman, Dina E. M. Mohamed, Khlood A. A. Abdeljawaad, Mohamed Ahmed Naeem, Gamal A. Gabr, Ahmed M. Shawky, Mahmoud E. S. Soliman, Peter A. Sidhom, Paul W. Paré and Mohamed-Elamir F. Hegazy
Viruses 2023, 15(1), 250; https://doi.org/10.3390/v15010250 - 15 Jan 2023
Cited by 3 | Viewed by 2233
Abstract
The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic [...] Read more.
The emergence of the Coronavirus Disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 6 million deaths. The 3C-like protease (3CLpro) enzyme of the SARS-CoV-2 virus is an attractive druggable target for exploring therapeutic drug candidates to combat COVID-19 due to its key function in viral replication. Marine natural products (MNPs) have attracted considerable attention as alternative sources of antiviral drug candidates. In looking for potential 3CLpro inhibitors, the MNP database (>14,000 molecules) was virtually screened against 3CLpro with the assistance of molecular docking computations. The performance of AutoDock and OEDocking software in anticipating the ligand-3CLpro binding mode was first validated according to the available experimental data. Based on the docking scores, the most potent MNPs were further subjected to molecular dynamics (MD) simulations, and the binding affinities of those molecules were computed using the MM-GBSA approach. According to MM-GBSA//200 ns MD simulations, chetomin (UMHMNP1403367) exhibited a higher binding affinity against 3CLpro than XF7, with ΔGbinding values of −55.5 and −43.7 kcal/mol, respectively. The steadiness and tightness of chetomin with 3CLpro were evaluated, revealing the high stabilization of chetomin (UMHMNP1403367) inside the binding pocket of 3CLpro throughout 200 ns MD simulations. The physicochemical and pharmacokinetic features of chetomin were also predicted, and the oral bioavailability of chetomin was demonstrated. Furthermore, the potentiality of chetomin analogues –namely, chetomin A-D– as 3CLpro inhibitors was investigated. These results warrant further in vivo and in vitro assays of chetomin (UMHMNP1403367) as a promising anti-COVID-19 drug candidate. Full article
(This article belongs to the Special Issue Viral Enzyme Inhibitors: Structure and Dynamics)
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11 pages, 2899 KiB  
Article
Structural Basis for the Inhibition of Coronaviral Main Proteases by a Benzothiazole-Based Inhibitor
by Xiaohui Hu, Cheng Lin, Qin Xu, Xuelan Zhou, Pei Zeng, Peter J. McCormick, Haihai Jiang, Jian Li and Jin Zhang
Viruses 2022, 14(9), 2075; https://doi.org/10.3390/v14092075 - 18 Sep 2022
Cited by 9 | Viewed by 1989
Abstract
The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants [...] Read more.
The ongoing spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused hundreds of millions of cases and millions of victims worldwide with serious consequences to global health and economies. Although many vaccines protecting against SARS-CoV-2 are currently available, constantly emerging new variants necessitate the development of alternative strategies for prevention and treatment of COVID-19. Inhibitors that target the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation, represent a key class of antivirals. Here, we showed that a peptidomimetic compound with benzothiazolyl ketone as warhead, YH-53, is an effective inhibitor of SARS-CoV-2, SARS-CoV, and MERS-CoV Mpros. Crystal structures of Mpros from SARS-CoV-2, SARS-CoV, and MERS-CoV bound to the inhibitor YH-53 revealed a unique ligand-binding site, which provides new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures defined the key molecular determinants required for inhibition and illustrate the binding mode of Mpros from other coronaviruses. In consideration of the important role of Mpro in developing antivirals against coronaviruses, insights derived from this study should add to the design of pan-coronaviral Mpro inhibitors that are safer and more effective. Full article
(This article belongs to the Special Issue Viral Enzyme Inhibitors: Structure and Dynamics)
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