Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport (R) database (similar to 7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood-brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (Delta G) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best Delta G value of -8.540 Kcal/mol, followed by MolPort-002-693-933 with Delta G = -8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.

Automated summary

This study aimed to identify potential inhibitors for SARS-CoV-2 ACE2 receptors and investigate their mechanism of action using molecular modeling and theoretical determination of biological activity. Through virtual screening and docking studies, several molecules with antiviral potential were identified. The pharmacokinetic and toxicological studies showed these molecules to have low toxicity and good bioavailability.