Identification of Plant-Based Drug-like Molecules as Potential Inhibitors against hACE2 and S-RBD of SARS-CoV-2 using Multi-step Molecular Docking and Dynamic Simulation Approach.

Abstract There has been considerable interest to develop effective antiviral drugs with substantial efficacy to the varying lineage of SARS-CoV-2. The plant-based bioactive molecules (phytochemicals) have proven to exhibit promising therapeutic efficacy and immune-modulatory effect due to their inherent broad-spectrum biological properties such as antioxidant, antiviral, and anti-inflammatory with minimal or no side effects. The SARS-CoV-2 infection is initiated upon recognition and binding of the spike (S) Receptor-Binding Domain (RBD) to the host cell surface receptor, human Angiotensin-Converting Enzyme 2 (hACE2). Therefore, the underlying mechanism of interaction between host cell receptors and blocking the virus-cell interaction is considered to be a promising approach for the management and treatment of COVID-19 disease. In the present study, In-silico screening of phytochemicals against two targets of SARS-CoV-2 using a multi-step molecular docking approach was investigated. Based on the Glide-XP docking score, the top 5 molecules were subjected to steered molecular dynamics (SMD) simulation for calculation of binding force, and work done to get mechanistic insight has been carried out. Further, the op 3 ligands with the highest force and work were subjected to molecular dynamics simulation and binding free energy evaluations. The results revealed that the protein-ligand complexes showed stable trajectories throughout the 100 ns simulation. Moreover, the drug likeliness predicted by pKi, LE, ADMET analysis, and Pa & Pi values suggested that the best 3 lead molecules for both the targets (ACE2: Rosavin, Isoorientin, Palasitrin) & (RBD: Cinnamtannin B1, Isoskimmiwallin, Terflavin A) have good inhibitory efficiency, better pharmacokinetics, and are non-toxic under physiological conditions. Thus, these molecules can be used as potential therapeutic drugs against SARS-CoV-2 infection.