Identification of potent inhibitors against transmembrane serine protease 2 for developing therapeutics against SARS-CoV-2.

In viral binding and entry, the Spike(S) protein of SARS-CoV-2 uses transmembrane serine protease 2 (TMPRSS2) for priming to cleavage themselves. In this study, we have screened 'drug-like' 7476 ligands and found that over thirty ligands can effectively inhibit the TMPRSS-2 better than the control ligand. Finally, the three best drug agents L1, L2, and L6 were selected according to their average binding affinities and fitting score. These ligands interact with Asp435, Cys437, Ser436, Trp461, and Cys465 amino acid residues. The three best candidates and a reported drug Nafamostat mesylate (NAM) were selected to run 250 ns molecular dynamics (MD) simulations. Various properties of ligand-protein interactions obtained from MD simulation such as bonds, angle, dihedral, planarity, coulomb, and van der Waals (VdW) were used for principal component analysis (PCA) calculation. PCA discloses the evidence of the structural similarities to the corresponding complexes of L1, L2, and L6 with the complex of TMPRSS2(TM) and Nafamostat mesylate (TM-NAM). Moreover, Quantitative structure-activity relationship (QSAR) pattern recognition was generated using PCA for the investigation of structural similarities among the selected ligands. Multiple Linear Regression (MLR) model was built to predict the binding energy compared to the binding energy obtained from molecular docking. The MLR regression model reveals an accuracy of 80% for the prediction of the binding energy of ligands. ADMET analysis demonstrates that these drug agents are appeared to be safer inhibitors. These three ligands can be used as potential inhibitors against the TMPRSS2.Communicated by Ramaswamy H. Sarma.

Phytochemicals-based targeting RdRp and main protease of SARS-CoV-2 using docking and steered molecular dynamic simulation: A promising therapeutic approach for Tackling COVID-19.

The ongoing COVID-19 pandemic has affected millions of people worldwide and caused substantial socio-economic losses. Few successful vaccine candidates have been approved against SARS-CoV-2; however, their therapeutic efficacy against the mutated strains of the virus remains questionable. Furthermore, the limited supply of vaccines and promising antiviral drugs have created havoc in the present scenario. Plant-based phytochemicals (bioactive molecules) are promising because of their low side effects and high therapeutic value. In this study, we aimed to screen for suitable phytochemicals with higher therapeutic value using the two most crucial proteins of SARS-CoV-2, the RNA-dependent RNA polymerase (RdRp) and main protease (Mpro). We used computational tools such as molecular docking and steered molecular dynamics simulations to gain insights into the different types of interactions and estimated the relative binding forces between the phytochemicals and their respective targets. To the best of our knowledge, this is the first report that not only involves a search for a therapeutic bioactive molecule but also sheds light on the mechanisms underlying target inhibition in terms of calculations of force and work needed to extractthe ligand from the pocket of its target. The complexes showing higher binding forces were subjected to 200 ns molecular dynamic simulations to check the stability of the ligand inside the binding pocket. Our results suggested that isoskimmiwallin and terflavin A are potential inhibitors of RdRp, whereas isoquercitrin and isoorientin are the lead molecules against Mpro. Collectively, our findings could potentially aid in the development of novel therapeutics against COVID-19.