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

Structural Basis for the Acylation Reaction of Alphacoronavirus 3C-like Protease DOI
Junwei Zhou, Jiyao Chen, Peng Sun

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(11), P. 8330 - 8342

Published: May 14, 2024

Coronavirus 3C-like proteases (3CLpro) are critical for viral replication and provide targets antiviral drugs. Using the enteropathogenic alphacoronavirus porcine epidemic diarrhea virus (PEDV) as a model, we determined crystal structure of an inactive PEDV 3CLpro variant (C144A) in complex with peptide NF-κB essential modulator (NEMO227–233). Structural characterization showed that conformational change to S1′ pocket conferred tolerance nonconventional P1′-Val from NEMO substrate, indicating strong substrate accommodation. combination classical quantum mechanics/molecular mechanics simulations, explored free-energy landscapes associated acylation step regard various substrates. The P1′ site plays key role thermodynamics kinetics proteolysis, might affect cost reaction. Our study provides structural insight into coronavirus 3CLpro-mediated cleavage will inform development anti-coronavirus

Language: Английский

Citations

0
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.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 12, 2022

Abstract The SARS-CoV-2 main protease (M pro ) plays an essential role in the coronavirus lifecycle by catalysing hydrolysis of viral polyproteins at specific sites. M is target drugs, such as nirmatrelvir, though resistant mutants have emerged that threaten drug efficacy. Despite its importance, questions remain on mechanism how binds substrates. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to evaluate structural and responses presence absence a substrate. results highlight communication between dimer subunits identify networks, including some far from active site, link site with known allosteric inhibition or which are associated nirmatrelvir resistance. They imply mutations enable resistance altering behaviour . More generally, show utility D-NEMD technique for identifying functionally relevant sites networks those

Language: Английский

Citations

1
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

Citations

0