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.
Arpana Parihar, Zannatul Ferdous Sonia, Nishant Kumar Choudhary, Palak Sharma, Iktedar Mahdi, Fuad Taufiqul Hakim, Muhammad Ali, Raju Khan, Mohammed S. Alqahtan, Mohamed Abd Elhamid Abbas · Research Square · 2022
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.