Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study

hLife, Journal Year: 2024, Volume and Issue: 2(8), P. 419 - 433

Published: June 15, 2024

During the continuing evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Omicron variant concern emerged in second half 2021 and has been dominant since November that year. Along with its sublineages, it maintained a prominent role ever since. The Nsp5 main protease (Mpro) virus is characterized by single mutation, P132H. Here we determined X-ray crystal structures P132H mutant (or O-Mpro) as free enzyme complex Mpro inhibitor, alpha-ketoamide 13b-K, conducted enzymological, biophysical well theoretical studies to characterize O-Mpro. We found O-Mpro similar overall structure binding 13b-K; however, displays lower enzymatic activity thermal stability compared WT-Mpro (with "WT" referring prototype strain). Intriguingly, imidazole ring His132 carboxylate plane Glu240 are stacked configuration here. Empirical folding energy calculations suggest dimer destabilized relative due less favorable van der Waals interactions backbone conformations individual protomers. All-atom continuous constant-pH molecular dynamics (MD) simulations reveal display coupled titration. At pH 7, predominantly neutral respect which charged. In order examine whether mutation eases emergence further mutations, also analyzed P132H+T169S double mutant, characteristic BA.1.1.2 lineage. However, little evidence correlation between two sites.

Language: Английский

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Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Bio-Logical and Pharmacological Profiling

Published: June 19, 2024

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due its ability evolve and generate new subvariants, leading waves of infection. Additionally, other coronaviruses like Middle East (MERS-CoV, formerly known as hCoV-EMC) which first emerged in 2012, persists present severe illness humans. The continued identification novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises possibility clades concern emerging. As result, there is pressing need pan-CoV therapeutic drugs vaccines. After extensive optimization an HCV protease inhibitor screening hit, 3CLPro (MK-7845) was discovered subsequently profiled. MK-7845 exhibited nanomolar vitro potency broad spectrum activity against panel clinical SARS-CoV-2 subvariants MERS-CoV. Furthermore, when administered orally, demonstrated notable reduction viral burdens by >6 log orders lungs transgenic mice infected (K18-hACE2 mice) MERS-CoV (K18-hDDP4 mice).

Language: Английский

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In Silico Comparative Analysis of Ivermectin and Nirmatrelvir Inhibitors Interacting with the SARS-CoV-2 Main Protease

Biomolecules, Journal Year: 2024, Volume and Issue: 14(7), P. 755 - 755

Published: June 25, 2024

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which a potent inhibitor that targets SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, broad-spectrum antiparasitic drug, has demonstrated effectiveness against virus laboratory settings. However, its clinical implications are still debated. Using computational methods, such molecular docking and 100 ns dynamics simulations, we investigated how Nirmatrelvir Ivermectin interacted with Mpro(A). Calculations using density functional theory were instrumental elucidating behavior of isolated molecules, primarily analyzing frontier orbitals. Our analysis revealed distinct binding patterns: formed strong interactions amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, ASN142, showing stable binding, root-mean-square deviation (RMSD) around 2.0 Å. On other hand, THR237, THR239, LEU271, LEU272, LEU287, displaying RMSD 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), stability persistent despite forming fewer hydrogen bonds. These findings offer detailed insights into bind to main protease, providing valuable information for potential strategies COVID-19.

Language: Английский

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Asymmetric imidazole-4,5-dicarboxamides derivatives as SARS-CoV-2 main protease inhibitors: Design, Synthesis and Biological Evaluation

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Novel asymmetric imidazole-4,5-dicarboxamide derivatives were synthesized, evaluated for SARS-CoV-2 M Pro inhibitory activity in vitro , and investigated binding ability silico .

Language: Английский

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Peptidomimetic Analogues Act as Effective Inhibitors against SARS-CoV-2 by Blocking the Function of Cathepsin L

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(19), P. 17124 - 17143

Published: Sept. 18, 2024

Cathepsin L (CatL) is a promising antiviral drug target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as an important protease for cleaving the SARS-CoV-2 spike protein and enhancing viral entry to cells. We identified tripeptide aldehyde candidate,

Language: Английский

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