Targeting the SARS-CoV-2 main protease using FDA-approved Isavuconazonium, a P2-P3 ?-ketoamide derivative and Pentagastrin: An in-silico drug discovery approach.

ABSTRACT: The SARS-CoV-2 main protease (Mpro) is an attractive target towards discovery of drugs to treat COVID-19 because of its key role in virus replication. The atomic structure of Mpro in complex with an ?-ketoamide inhibitor (Lig13b) is available (PDB ID:6Y2G). Using 6Y2G and the prior knowledge that protease inhibitors could eradicate COVID-19, we designed a computational study aimed at identifying FDA-approved drugs that could interact with Mpro. We searched the DrugBank and PubChem for analogs and built a virtual library containing ?33,000 conformers. Using high-throughput virtual screening and ligand docking, we identified Isavuconazonium, a ketoamide inhibitor (?-KI) and Pentagastrin as the top three molecules (Lig13b as the benchmark) based on docking energy. The ?Gbind of Lig13b, Isavuconazonium, ?-KI, Pentagastrin was -28.1, -45.7, -44.7, -34.8 kcal/mol, respectively. Molecular dynamics simulation revealed that these ligands are stable within the Mpro active site. Binding of these ligands is driven by a variety of non-bonded interaction, including polar bonds, H-bonds, van der Waals and salt bridges. The overall conformational dynamics of the complexed-Mpro was slightly altered relative to apo-Mpro. This study demonstrates that three distinct classes molecules, Isavuconazonium (triazole), ?-KI (ketoamide) and Pentagastrin (peptide) could serve as potential drugs to treat patients with COVID-19.

SUBMITTER: Achilonu I 

PROVIDER: S-EPMC7462840 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature