Comprehensive 3D-QSAR and Binding Mode of DAPY Inhibitors Using R-group Search and Molecular Docking

摘要

The diarylpyrimidine (DAPY) compounds are important in the nonnucleoside reverse enzyme inhibitors.The present study is aimed at studying the three-dimensional quantitative structure-activity relationship (3D-QSAR) of DAPY inhibitors and their binding mode.We build a 3D-QSAR model involving 24 training DAPY inhibitors based on Topomer CoMFA,and 8 molecules are employed to validate the external predictive power of the model obtained.The multiple correlation coefficients of fitting,cross-validation and external validation were 0.979,0.597 and 0.756,respectively.Topomer Search was employed as a tool for virtual screening in drug-like compounds of ZINC database (2012).Finally,we successfully design 30 new molecules with higher activity than that of all training and test inhibitors.The results indicated that Topomer CoMFA model had both favorable estimation stability and good predictive capability.Topomer Search technology could be effectively used to screen and design new compound,and had good predictive capability to guide the design of new Anti-HIV drugs.The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HIV-1 reverse transcriptase active site,which revealed the likely bioactive conformations.This study showed extensive interactions between the DAPY derivatives and MET230,TRP229,PHE227,TYR318,TYR183,PRO95,GLY99,ILE100,TYR188,VAL106,TYR181,GLY190,GLU138,VAL179,THR139,ASN103 and LYS101 residues in the active site of HIV-1 reverse transcriptase.These results provide useful insights for the design of potent new inhibitors of HIV-1 reverse transcriptase.