Molecular Simulation And Virtual Screening Of PD-1/PD-L1 Inhibitors

With the development of immunotherapy,key advances have been made in the treatment of cancer.Especially,the successful launch of multiple checkpoint PD-1/PD-L1 antibodies has brought hope to cancer patients.It is of great significance to develop PD-1/PD-L1 small molecule inhibitors,Considering the advantages of small molecule drugs over antibody drugs,including convenience of oral administration,flexible drug exposure and low price.Unfortunately,currently there are less known PD-1/PD-L1 small molecular inhibitors,and the structure types are relatively single.Therefore,based on the mechanism of PD-L1 dimerization induced by small molecule inhibitors,this project explored the structural characteristics of dimeric PD-L1 through dynamic simulation,and proposed a virtual screening protocol for the PD-1/PD-L1 system.First,we explored the dynamic simulation of PD-L1 dimerization induced by small molecule inhibitors.The crystal structure of the dimeric PD-L1 complex with molecules:LH1307?BMS1166?BMS1001?BMS202?BMS200?BMS37 and BMS8 from PDB database were selected for 100ns dynamic simulation.The RMSD?RMSF?Per-residue free energy decomposition and pairwise per-residue free energy decomposition were analyzed.The RMSD and RMSF results show that the structure of the complex with ligand BMS8 is relatively unstable,the residues in Dimeric PD-L1 Loop region fluctuates greatly and its structure is unstable.In terms of binding free energy,the higher activity of the ligand,the smaller the binding free energy;In ligand contact surface of dimeric PD-L1,the Ile37,Tyr39,Met98,Ala104,Tyr106,Ile155,Tyr157,Met216,Ala222 and Tyr224 residues contribute a large amount of binding free energy and are considered to play a key role in the binding of the ligand receptor;Besides,pairwise per-residues with significant energy contribution in protein-protein interaction were obtained.Then,based on the above analysis results.Starting from three commercially available databases Specs Chemdiv and Enamine,two virtual screening processes were designed.?1?Focus on the common asymmetric inhibitors with Dimeric PD-L1,the crystal structure of PDB ID:6R3K is selected as the receptor protein.Using Surflex-sim tool for molecular superposition,BMS1166 molecule and Compound 17 molecule as templates,30000 molecules with the highest score were selected.Then using Autodock Vina,MOE and Schr?dinger for consistent docking.?2?Because of the C₂ symmetry phenomenon of Dimeric PD-L1 system,PDB ID:6RPG is selected as the receptor protein.Using Pipeline pilot 8.5 and Python to distinguish symmetry molecules.For the obtained symmetric molecules,MOE and Schr?dinger were used for consistent docking.All the docking result data was analyzed by empirical method,then 433molecules were selected for 10ns dynamic simulation to optimize the screening results.Finally,141 candidate compounds were obtained.These compounds were tested for enzymatic activity using the HTRF method.This paper explored the characteristics of dimeric PD-L1 structure,analyzed the key residue interactions between ligand-receptors and dimeric proteins.The paper also constructed a virtual screening process.The research is helpful for understanding the structural characteristics and mechanism of dimeric PD-L1,and has some guiding significance for the development of small molecule drugs targeting PD-L1.