QM/MM Simulations of the Covalent Inhibition of the SARS-CoV-2 Main Protease: Four Compounds and Three Reaction Mechanisms DOI Creative Commons
Bella L. Grigorenko, Igor V. Polyakov, Maria G. Khrenova

et al.

Published: March 2, 2023

The search for efficient inhibitors of the SARS-CoV-2 enzymes is ongoing due to continuing COVID-19 pandemic. We report results computational modeling reactions main protease (MPro ) with four potential covalent inhibitors. Two them, carmofur and nirmatrelvir, have been shown experimentally ability inhibit MPro . other compounds, X77A X77C, were designed computationally in this work, derived from structure X77, a non-covalent inhibitor forming tight surface complex modified X77 by introducing warheads capable chemical catalytic cysteine residue M Pro active site. reaction mechanisms molecules investigated quantum mechanics/molecular mechanics (QM/MM) calculations using large subsystems. First, at QM/MM level, we optimized structures stationary points on energy surfaces corresponding reactants, products, intermediates, transition states along hypothesized coordinates. Analysis these has informed selection collective variables subsequent Gibbs profiles molecular dynamics simulations potentials (QM/MM MD). In simulations, QM part was treated DFT PBE0 functional. show that all compounds form adducts Cys 145 From perspective, follow three distinct mechanisms. cases, initiated nucleophilic attack thiolate group deprotonated dyad Cys145-His41 case X77A, binding ligand accompanied formation fluoro-uracil leaving group. X77C follows aromatic substitution SN Ar mechanism. which reactive nitrile group, leads thioimidate adduct Cys145 enzyme

Language: Английский

Nirmatrelvir Resistance—de Novo E166V/L50V Mutations in an Immunocompromised Patient Treated With Prolonged Nirmatrelvir/Ritonavir Monotherapy Leading to Clinical and Virological Treatment Failure—a Case Report DOI
Neta S. Zuckerman,

Efrat Bucris,

Danielle Keidar-Friedman

et al.

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 78(2), P. 352 - 355

Published: Aug. 19, 2023

Abstract Resistance of SARS-CoV-2 to antivirals was shown develop in immunocompromised individuals receiving remdesivir. We describe an patient who treated with repeated and prolonged courses nirmatrelvir developed de-novo E166V/L50F mutations the Mpro region. These were associated clinical virological treatment failure.

Language: Английский

Citations

57
Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development DOI Creative Commons
Kwangho Nam, Yihan Shao, Dan Thomas Major

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 8, 2024

Understanding enzyme mechanisms is essential for unraveling the complex molecular machinery of life. In this review, we survey field computational enzymology, highlighting key principles governing and discussing ongoing challenges promising advances. Over years, computer simulations have become indispensable in study mechanisms, with integration experimental exploration now established as a holistic approach to gain deep insights into enzymatic catalysis. Numerous studies demonstrated power characterizing reaction pathways, transition states, substrate selectivity, product distribution, dynamic conformational changes various enzymes. Nevertheless, significant remain investigating multistep reactions, large-scale changes, allosteric regulation. Beyond mechanistic studies, modeling has emerged an tool computer-aided design rational discovery covalent drugs targeted therapies. Overall, design/engineering drug development can greatly benefit from our understanding detailed enzymes, such protein dynamics, entropy contributions, allostery, revealed by studies. Such convergence different research approaches expected continue, creating synergies research. This outlining ever-expanding research, aims provide guidance future directions facilitate new developments important evolving field.

Language: Английский

Citations

24
Dynamical Nonequilibrium Molecular Dynamics Simulations Identify Allosteric Sites and Positions Associated with Drug Resistance in the SARS-CoV-2 Main Protease DOI Creative Commons
H. T. Henry Chan, A. Sofia F. Oliveira, Christopher J. Schofield

et al.

JACS Au, Journal Year: 2023, Volume and Issue: 3(6), P. 1767 - 1774

Published: June 7, 2023

The SARS-CoV-2 main protease (M

Language: Английский

Citations

30
Discovery of procyanidin condensed tannins of (−)-epicatechin from Kratom, Mitragyna speciosa, as virucidal agents against SARS-CoV-2 DOI
Sanya Sureram, Nopporn Chutiwitoonchai,

Tam Pooprasert

et al.

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 273, P. 133059 - 133059

Published: June 10, 2024

Language: Английский

Citations

10
Multiscale Simulations of the Covalent Inhibition of the SARS-CoV-2 Main Protease: Four Compounds and Three Reaction Mechanisms DOI
Bella L. Grigorenko, Igor V. Polyakov, Maria G. Khrenova

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(24), P. 13204 - 13214

Published: June 9, 2023

We report the results of computational modeling reactions SARS-CoV-2 main protease (MPro) with four potential covalent inhibitors. Two them, carmofur and nirmatrelvir, have shown experimentally ability to inhibit MPro. other compounds, X77A X77C, were designed computationally in this work. They derived from structure X77, a non-covalent inhibitor forming tight surface complex modified X77 by introducing warheads capable reacting catalytic cysteine residue MPro active site. The reaction mechanisms molecules investigated quantum mechanics/molecular mechanics (QM/MM) simulations. show that all compounds form adducts Cys 145 From chemical perspective, these follow three distinct mechanisms. are initiated nucleophilic attack thiolate group deprotonated dyad Cys145–His41 In case X77A, binding ligand is accompanied formation fluoro-uracil leaving group. X77C follows aromatic substitution SNAr mechanism. nirmatrelvir (which has reactive nitrile group) leads thioimidate adduct Cys145 enzyme Our contribute ongoing search for efficient inhibitors enzymes.

Language: Английский

Citations

16
Dynamical nonequilibrium molecular dynamics simulations reveal allosteric networks, signal transduction mechanisms, and sites associated with drug resistance in biomolecular systems DOI Creative Commons

Balazs Balega,

Michael Beer, James Spencer

et al.

Molecular Physics, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 16, 2024

Language: Английский

Citations

5
A Reflection on the Use of Molecular Simulation to Respond to SARS-CoV-2 Pandemic Threats DOI Creative Commons
Lorenzo Casalino, Carlos A. Ramos‐Guzmán, Rommie E. Amaro

et al.

The Journal of Physical Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 3249 - 3263

Published: March 21, 2025

Molecular simulations play important roles in understanding the lifecycle of SARS-CoV-2 virus and contribute to design development antiviral agents diagnostic tests for COVID. Here, we discuss insights that such have provided challenges involved, focusing on main protease (Mpro) spike glycoprotein. Mpro is leading target antivirals, while glycoprotein vaccine design. Finally, reflect lessons from this pandemic simulation community. Data sharing initiatives collaborations across international research community contributed advancing knowledge should be built help future pandemics other global as antimicrobial resistance.

Language: Английский

Citations

0
Enhancing the understandings on SARS-CoV-2 main protease (Mpro) mutants from molecular dynamics and machine learning DOI
Jiawen Wang, Juan Xie,

Yi Yu

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 143076 - 143076

Published: April 1, 2025

Language: Английский

Citations

0
Subpocket-Based Analysis Approach for the Protein Pocket Dynamics DOI
Nan Lv, Zexing Cao

Journal of Chemical Theory and Computation, Journal Year: 2024, Volume and Issue: 20(11), P. 4909 - 4920

Published: May 21, 2024

Structural and dynamic characteristics of protein pockets remarkably influence their biological functions are also important for enzyme engineering new drug research development. To date, several softwares have been developed to analyze the properties pockets. However, due complexity diversity pocket information during kinetic relaxation, further improvement capacity expansion current tools required. Here, we a platform software AlphaTraj in which computational strategy that divides whole into subpockets examines various such as survival time, stability, correlation was proposed implemented. We scoring function well visualize quality pocket. Furthermore, implemented automated conformational search ligand docking optimization. These may help us gain deep understanding accelerate design inhibitors small-molecule drugs. The is freely available at https://github.com/dooo12332/AlphaTraj.git under GNU GPL license.

Language: Английский

Citations

2
Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations DOI
Muya Xiong, Tianqing Nie,

Zhewen Li

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 28, 2024

3-Chymotrypsin-like protease (3CLpro) is a prominent target against pathogenic coronaviruses. Expert knowledge of the cysteine-targeted covalent reaction mechanism crucial to predict inhibitory potency approved inhibitors 3CLpros SARS-CoV-2 variants and perform structure-based drug design newly emerging We carried out an extensive array classical hybrid QM/MM molecular dynamics simulations explore inhibition mechanisms five well-characterized toward 3CLpro its mutants. The calculated binding affinity reactivity are highly consistent with experimental data, predicted L167F, E166V, or T21I/E166V mutant in full agreement IC50s determined by accompanying enzymatic assays. explored unveil impact residue mutagenesis on structural that communicates change not only noncovalent strength but also free energy. Such inhibitor dependent, corresponding varied levels resistance these mutants nirmatrelvir simnotrelvir no 11a compound. These results together suggest present suitable protocol can efficiently evaluate along elucidated inhibition.

Language: Английский

Citations

2