In-silico screening and molecular dynamics analysis to uncover mechanistic of natural SARS-CoV-2 inhibitors present in four medicinal plants

SARS-CoV-2 is a viral pathogen that claimed millions of lives during the recent pandemic. Despite the effectiveness of clinical interventions in preventing this infection, there are currently no specific drugs available for treatment. Interestingly, repurposed AYUSH-64, a polyherbal antimalarial formulation, shows astounding clinical success rates for COVID-19 management. Here we applied computer-aided drug design tools to uncover plausible therapeutic potential of bioactive secondary metabolites present in four medicinal plants of AYUSH-64. Accordingly, virtual screening against four principal drug target proteins [3CL ^pro , RdRp, receptor binding domain (RBD) and PL ^pro ] of SARS-CoV-2 indicates their effective binding at the active site catalytic clefts of these target proteins, which is further supported by 3D-convolutional neural network-based affinity predictions and MMPB/GBSA binding free energy calculation, Molecular dynamic simulation and ADMET profiling. Based on molecular docking and binding affinity results, the most effective phytochemicals for each target are picrorhizoside B for 3CL ^pro and RdRp with binding energies of -8.5 and -11.2 Kcal/mol, respectively and 6-hydroxykaempferol 7-(6''-(E)-caffeylglucoside for PL ^pro and alstoniasidine B for RBD with their respective binding energies -8.6 and -8.7 Kcal/mol. Detailed structure-guided plausible mode of action along with their predicted pharmacokinetic profiles have been presented herein to divulge the anti-SARS-CoV-2 potential of AYUSH-64.