Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 M pro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation

• Published in: International journal of molecular sciences Vol. 25; no. 11
• Main Authors: Peralta-Moreno, Maria Nuria, Mena, Yago, Ortega-Alarcon, David, Jimenez-Alesanco, Ana, Vega, Sonia, Abian, Olga, Velazquez-Campoy, Adrian, Thomson, Timothy M, Pinto, Marta, Granadino-Roldán, José M, Santos Tomas, Maria, Perez, Juan J, Rubio-Martinez, Jaime
• Format: Journal Article
• Language: English
• Published: Switzerland 01.06.2024
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Coronavirus 3C Proteases - antagonists & inhibitors; Coronavirus 3C Proteases - chemistry; Coronavirus 3C Proteases - metabolism; COVID-19 - virology; Drug Discovery - methods; Drug Evaluation, Preclinical - methods; High-Throughput Screening Assays - methods; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; docking; virtual screening; drug design; MMPB/GBSA approach; molecular dynamics; dark chemical matter; SARS-CoV-2 main protease
• ISSN: 1422-0067

The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (M ) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a value of 48 ± 5 μM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.