Progress in Research on Inhibitors Targeting SARS-CoV-2 Main Protease (M^pro)

ACS Omega, Journal Year: 2024, Volume and Issue: 9(32), P. 34196 - 34219

Published: Aug. 2, 2024

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), by SARS-CoV-2 its variants, further highlighted urgent need for development effective therapeutic agents. Currently, highly conserved broad-spectrum nature main proteases (M

Language: Английский

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In Silico Discovery of SARS-CoV-2 Main Protease Inhibitors Using Docking, Molecular Dynamics, and Fragment Molecular Orbital Calculations

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: 129(6), P. 1740 - 1749

Published: Jan. 31, 2025

The 3C-like protease of severe acute respiratory syndrome coronavirus 2, known as the main (Mpro), is an attractive drug target for treatment disease 2019. This study reports discovery novel Mpro inhibitors using several in silico techniques, including docking, molecular dynamics (MD), and fragment orbital (FMO) calculations. We performed docking calculations on 5950 compounds with bioactivity, 12 were selected. An enzymatic assay was conducted, revealing that BP-1-102 exhibits significant inhibitory activity IC50 11.1 μM. identification seed from experiments a few demonstrates effectiveness our Furthermore, detailed analyses MD FMO suggested interaction mechanism which hydroxyl group forms hydrogen bond E166 Mpro. SH-4-54, derivative without aforementioned group, investigated observed to be significantly reduced, 81.5 result strongly supports mechanism.

Language: Английский

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On the dual role of (+)-catechin as primary antioxidant and inhibitor of viral proteases

Computers in Biology and Medicine, Journal Year: 2024, Volume and Issue: 180, P. 108953 - 108953

Published: July 31, 2024

Natural antioxidants have become the subject of many investigations due to role that they play in reduction oxidative stress. Their main scavenging mechanisms concern direct inactivation free radicals and coordination metal ions involved Fenton-like reactions. Recently, increasing attention has been paid non-covalent inhibition enzymes different diseases by antioxidants. Here, a computational investigation on primary antioxidant power (+)-catechin against

Language: Английский

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Discovery of Potent Covalent CRM1 Inhibitors Via a Customized Structure-Based Virtual Screening Pipeline and Bioassays

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

Published: Oct. 3, 2024

CRM1 (chromosomal region maintenance 1, also referred to as exportin 1 or XPO1) plays a crucial role in maintaining the appropriate nuclear levels of tumor suppressor proteins (TSPs), growth regulatory (GRPs), and antiapoptotic proteins, thereby contributing significantly their anticancer effects. Dysregulation CRM1-mediated transport, observed range cancers such colon cancer well autoimmune diseases, highlights its significance various disease processes. In this paper, we employed customized structure-based virtual screening campaign search for novel covalent inhibitors purchased 50 potentially active compounds vitro bioassays. Among these candidates, AN-988 displayed notably higher binding affinity (

Language: Английский

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Molecular Mechanism-Driven Discovery of Novel Small Molecule Inhibitors against Drug-Resistant SARS-CoV-2 M^pro Variants

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(20), P. 7998 - 8009

Published: Oct. 10, 2024

Under the selective pressure of nirmatrelvir, a peptidomimetic covalent drug targeting SARS-CoV-2 Mpro, various drug-resistant mutations on Mpro have been acquired in vitro. Among mutations, L50F and E166V, along with combination are particularly representative pose considerable obstacles to effective treatment COVID-19. Our previous study identified NMI-001 NMI-002 as novel nonpeptide inhibitors that target possessing unique scaffolds binding modes different from those nirmatrelvir. In view these findings, we proposed design strategy aimed at rapidly identifying can combat mutation-induced resistance. Initially, molecular dynamics (MD) simulation was employed investigate mechanisms against three mutants (Mpro_L50F, Mpro_E166V, Mpro_L50F+E166V). Then, conducted two phases high-throughput virtual screening. first phase, served template perform scaffold hopping-based similarity search library 15,742,661 compounds. second 968 compounds exhibiting were evaluated via docking MD simulations. Six may be least one mutant identified, five procured for conducting vitro assays. Finally, compound Z1557501297 (NMI-003) inhibitory effects E166V (IC50 = 27.81 ± 2.65 μM) L50F+E166V 8.78 0.74 discovered. The referring NMI-003-Mpro_E166V NMI-003-Mpro_L50F+E166V further elucidated atomic level. summary, NMI-003 reported herein is activity L50F+E166V, which provides good starting point antiviral drugs SARS-CoV-2.

Language: Английский

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Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 M^pro Inhibitors from Large Chemical Libraries

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(6), P. 1984 - 1995

Published: March 12, 2024

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main Protease (Mpro) is an enzyme that cleaves viral polyproteins translated from the genome and critical for replication. Mpro a target anti-SARS-CoV-2 drug development, multiple crystals complexed with competitive inhibitors have been reported. In this study, we aimed to develop consensus pharmacophore as tool expand search inhibitors. We generated model by aligning summarizing pharmacophoric points 152 bioactive conformers of SARS-CoV-2 Validation against library subset ligands showed our retrieved poses reproduced crystal-binding mode in 77% cases. Using models derived pharmacophore, screened >340 million compounds. Pharmacophore-matching chemoinformatics analyses identified new potential candidate compounds were chemically dissimilar reference set, among them, demonstrating relevance model. evaluated effect 16 candidates on enzymatic activity finding seven inhibitory activity. Three (1, 4, 5) had IC50 values midmicromolar range. reported herein can be used identify improved novel chemical scaffolds Mpro. method developed its generation provided open-access code (https://github.com/AngelRuizMoreno/ConcensusPharmacophore) applied other pharmacological targets.

Language: Английский

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Systematic insight into the dual COX-2/5-LOX inhibitory mechanism of Duhuo Jisheng decoction for treatment of osteoarthritis based on in silico and bioassay

Journal of Ethnopharmacology, Journal Year: 2024, Volume and Issue: 340, P. 119263 - 119263

Published: Dec. 18, 2024

Language: Английский

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