A Molecular Docking Approach to Identify Effective Stilbene Derivatives Against the Main Protease of Sars Cov-2

Main protease (M^pro) or 3-chymotrypsin-like cysteine protease (3CL^pro) has always been an attractive antiviral therapeutic target due to its pivotal role played in viral replication, transcription and in polyprotein processing. Being highly conserved in various coronavirus (CoVs), it is less susceptible to mutation induced drug resistance. Drugs targeting M^pro protein bears promising prospects against SARS-CoV 2, the strain of coronavirus responsible for the Covid-19 pandemic. Stilbene derivatives have previously been found to inhibit the replication of SARS-CoV in vitro. In this study, 17 stilbene derivatives were substituted by hydroxyl, methoxy and methyl at various positions of the aromatic rings and some of the molecules had one benzene ring replaced by pyridine ring. They were then molecularly docked in silico against the SARS-CoV 2 M^pro in order to determine potential inhibitors of the M^pro. The molecules were optimized for docking by carrying out simulation and quantum mechanics calculations using the B-3LYP correlation function and newer Pople’s 6-311G basis set in Gaussian 09W program package. The crystal structure of M^pro (PDB ID: 6Y2G) was optimized, checked by Swiss-PDB viewer, a molecular visualization tool. The molecular docking was conducted using AutoDock Vina and focusing on the protein cleavage containing the catalytic dyads His41 and Cys145 of M^pro. The drug likeliness and pharmacokinetic properties of the derivative molecules are determined using SwissADME and admetSAR softwares which use predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness. Most of the stilbene derivative molecules showed significant binding with the catalytic dyads of M^pro and presented high binding affinities ranging from -6.6 to -5.6 kcal/mol. 3,3′,5,5′-Tetramethoxystilbene and 2′,5,5′,6-Tetrahyroxystilbene-2-nitrogen showed better binding affinity (-6.6 kcal/mol) amongst all molecules. These two stilbene derivatives were found to show improved pharmacokinetic and drug likeliness properties compared to the unsubstituted/unmodified stilbene molecule. Although molecular docking study shows higher binding of stilbene derivatives against the SARS CoV-2 M^pro, the efficacy of these molecules as promising drug candidates needs to be further verified by molecular dynamics and in vitro/in vivo studies.