Ligand-based quantitative structural assessments of SARS-CoV-2 3CL inhibitors: An analysis in light of structure-based multi-molecular modeling evidences.

Due to COVID-19, the whole world is undergoing a devastating situation, but treatment with no such drug candidates still has been established exclusively. In that context, 69 diverse chemicals with potential SARS-CoV-2 3CL inhibitory property were taken into consideration for building different internally and externally validated linear (SW-MLR and GA-MLR), non-linear (ANN and SVM) QSAR, and HQSAR models to identify important structural and physicochemical characters required for SARS-CoV-2 3CL inhibition. Importantly, 2-oxopyrrolidinyl methyl and benzylester functions, and methylene (hydroxy) sulphonic acid warhead group, were crucial for retaining higher SARS-CoV-2 3CL inhibition. These GA-MLR and HQSAR models were also applied to predict some already repurposed drugs. As per the GA-MLR model, curcumin, ribavirin, saquinavir, sepimostat, and remdesivir were found to be the potent ones, whereas according to the HQSAR model, lurasidone, saquinavir, lopinavir, elbasvir, and paritaprevir were the highly effective SARS-CoV-2 3CL inhibitors. The binding modes of those repurposed drugs were also justified by the molecular docking, molecular dynamics (MD) simulation, and binding energy calculations conducted by several groups of researchers. This current work, therefore, may be able to find out important structural parameters to accelerate the COVID-19 drug discovery processes in the future.