Targeting SARS-CoV-2 main protease: a comprehensive approach using advanced virtual screening, molecular dynamics, and in vitro validation.

Targeting SARS-CoV-2 main protease: a comprehensive approach using advanced virtual screening, molecular dynamics, and in vitro validation.

Publication date: Dec 21, 2024

The COVID-19 pandemic, driven by the SARS-CoV-2 virus, necessitates the development of effective therapeutics. The main protease of the virus, Mpro, is a key target due to its crucial role in viral replication. Our study presents a novel approach combining ligand-based pharmacophore modeling with structure-based advanced virtual screening to identify potential inhibitors of Mpro. We screened around 200 million compounds using this integrated methodology, resulting in a shortlist of promising compounds. These were further scrutinized through molecular dynamics simulations, revealing their interaction dynamics with Mpro. Subsequent in vitro assays using the Mpro enzyme identified two compounds exhibiting significant micromolar inhibitory activity. These findings provide valuable scaffolds for the development of advanced therapeutics targeting Mpro. The comprehensive nature of our approach, spanning computational predictions to experimental validations, offers a robust pathway for rapid and efficient identification of potential drug candidates against COVID-19.

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Concepts Keywords
Molecular Antiviral Agents
Pandemic Antiviral Agents
Therapeutics Coronavirus 3C Proteases
Valuable Coronavirus 3C Proteases
Viral COVID-19
COVID-19 Drug Treatment
Drug Evaluation, Preclinical
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Protease Inhibitors
Protease Inhibitors
SARS-CoV-2

Semantics

Type Source Name
disease MESH COVID-19 pandemic
disease IDO role
pathway KEGG Viral replication
pathway REACTOME Reproduction
disease MESH syndrome
disease MESH Emergency
disease IDO process
drug DRUGBANK Amino acids
drug DRUGBANK Water
drug DRUGBANK Coenzyme M
pathway REACTOME Metabolism
disease IDO site
drug DRUGBANK Spinosad
drug DRUGBANK Zinc
disease IDO protein
drug DRUGBANK Ademetionine
drug DRUGBANK Chloride ion
disease IDO algorithm
disease IDO production
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Glutamic Acid
disease IDO assay
drug DRUGBANK Edetic Acid
drug DRUGBANK Tretamine
pathway REACTOME Intestinal absorption
drug DRUGBANK Dimercaprol
drug DRUGBANK L-Valine
drug DRUGBANK Trestolone
drug DRUGBANK Troleandomycin
disease MESH clinical significance
drug DRUGBANK Ocimum tenuiflorum top
drug DRUGBANK (S)-Des-Me-Ampa
drug DRUGBANK Alpha-1-proteinase inhibitor
drug DRUGBANK Diethylstilbestrol
drug DRUGBANK Nonoxynol-9

Original Article

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