In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking

• Published in: International journal of molecular sciences Vol. 23; no. 7; p. 3987
• Main Authors: Vázquez-Mendoza, Luis Heriberto, Mendoza-Figueroa, Humberto L, García-Vázquez, Juan Benjamín, Correa-Basurto, José, García-Machorro, Jazmín
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 03.04.2022; MDPI
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding sites; Chemical bonds; Coronavirus 3C Proteases; Coronaviruses; Covalence; covalent inhibitors; COVID-19; COVID-19 Drug Treatment; Cysteine proteinase; Docking; Drug development; Drug Repositioning; Drugs; Enzymes; Epidemics; FDA approval; Gene expression; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Pharmacology; pharmacophore modeling; Protease; Protease inhibitors; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Proteinase; Proteinase inhibitors; Proteins; Respiratory diseases; RNA polymerase; SARS-CoV-2; SARS-CoV-2 Mpro; Scopolamine; Severe acute respiratory syndrome coronavirus 2; structure-based virtual screening; Therapeutic targets; Viruses; Warheads; pharmacophore modeling; covalent inhibitors; SARS-CoV-2 Mpro; drug repositioning; structure-based virtual screening
• DOI: 10.3390/ijms23073987
• ISSN: 1422-0067; 1661-6596

The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (M ) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of M . The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 M in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 M .