Computational Approach for Covalent Lead Identification against Spike Glycoprotein of SARS-CoV-2 (preprint)

ABSTRACT

Background: A global outbreak of coronavirus disease 19 (COVID-19) led researchers to investigate various active compounds that can inhibit the replication of SARS-CoV2 (severe acute respiratory syndrome coronavirus 2). The present work targets to evaluate small covalent synthetic molecules through a virtual screening and docking approach that can efficiently inhibit Spike Glycoprotein of SARS CoV2. Methods: We retrieved around 50,000 small covalent synthetic molecules through the American chemical society (CAS) database. The initial evaluation of these synthetic molecules depends on the ADMET screening. A Lipinski's Rule of Five (RO5) was also applied to find whether the drug met the criteria of good bioavailability. Then, the further selection was made through virtual screening using BIOVIA Discovery Studio. Further, comparison among top hits was performed via a docking approach based on the binding energy (kcal/mol) calculated using the AutoDock Vina plugin and Patch Dock-like docking engines. Finally, the selected top five molecules were compared for their binding efficiency with reference drugs like Favipiravir, Chloroquine, Ribavirin, Hydroxychloroquine (approved by the FDA), and molecules with better binding affinity than reference drugs was selected. Results: In the first tier of selection, 215 molecules were screened out, satisfying all the necessary conditions of RO5 and ADMET. Among 215 molecules screened, only 203 molecules were stable in structure to undergo the second tier of target-based virtual screening. Further, based upon the LibDock score generated by virtual screening, the top five molecules with the highest LibD score were selected. Molecular docking of these five selected compounds reveals compound2 (3-ethyl-5-propyladamantan-1-amine) with the best binding energy. Furthermore, we compared the binding affinity of 3-ethyl-5-propyladamantan-1-amine with reported drugs that show 3-ethyl-5-propyladamantan-1-amine as the most promising ligand efficient hydrogen bond interactions with amino acid residues of protein which provides more excellent stability in the docked region of the protein with efficient binding energy as compared to the reference molecule. Moreover, Compound2 also has a high oral bioavailability, non-mutagenicity, non-toxicity and follows all RO5 criteria. Conclusion: Thus, it has potential as an antiviral covalent synthetic molecule that may prevent the replication of spike protein. These findings are just preliminary selection to facilitate the upcoming tests from in vivo and in vitro studies.