Computational Study Of Mechanism And Discovery Of Drugs Against SARS-CoV-2

COVID-19 pandemic has spread throughout the world,causing more 100 million individuals infected and over two million death cases were reported.Thus,avtive drugs that can against SARS-CoV-2 are urged needed.The spike glycoprotein of SARS-CoV-2 meditades the process of visrs invading host cells.As a structural protein,spike glycoprotein is a very important target for neutralizing antibodies.The main protease of SARS-CoV-2 is essential for the vital activity and proteins required for the the virus must to be cleaved by the main protease to have normol functions.As a non-structural protein,the main protease is a key target for inhibitors discovery.In our work,we chose CC12.1,an antibody that provides potential protection from disease,as the main research object.Binding modes of the antibody were investigated and compared with RBD bound receptor ACE2.Key epitopes were revealed and a distal motif of RJBD(residue numbers 473-488)was demonstrated.Compared to the receptor ACE2,conformation of RBD could be better stabilized through additional interaction of antibody with the distal motif of RBD,which was further found driven by electrostatic complementarity.By further analysis of the extensive hydrogen-bonding networks,residues D405,K417,Y421,Y453,L455,R457,Y473,A475,N487,G502,Y505 of RBD were identified as key epitopes.Key residues that play a crucial role in the antibody specific binding were identified by relative binding free energy calculation.Mutations of VH V98E and VLG68D in CC12.1,which could significantly enhance the binding affinity of the antibody,were also proposed by comparison study.The development of peptide-like drugs is getting more and more attention.We constructed a methodology for predicting peptide-like ligand based on three-dimensional structures of proteins,and further verified it in the human serum albumin.Through fluorescence assay and isothermal titration microcalorimetry experiment,it is found that the predicted ligand H3 specifically binds to site I of human serum albumin,and the equilibrium dissociation constant is 5.40 ± 0.41 μM.Subsequently,the established methodology was used to predict ligands of the main protease of SARS-CoV-2,and three peptide-like ligands were obtained.By analyzing the predicted binding modes,we concluded that all three peptide-like ligands might bind to the main protease of SARS-CoV-2.This work uses molecular dynamics simulation to identify the key epitopes in SARS-CoV-2 receptor binding domain and give explanations for failure of neutralization antibody caused by specific residues mutations on structural basis.Two proposed point mutations on antibody provide feasible information for advanced antibody design.At the same time,a methodology based on molecular docking for predicting peptide-like ligands was constructed to discover inhibitors targeted to SARS-CoV-2 main protease.