Construction, Virtual Screening And Evaluation Of Scoring Function Based On TGF? Type I Receptor Inhibitor Pharmacophore

Due to the tremendous improvement of computing power and the rapid development of computational chemistry and computational biology,computer aided drug design(CADD)technology has been successfully applied to drug discovery,speeding up the research process and reducing the associated costs and risks.TGF?R? inhibitors as new therapeutic agents in the treatment of malignant tumor has been widely concerned.This topic tries to build appropriate screening model for molecular docking method based TGF?? receptor inhibitor by building a pharmacophore based on structure-activity relationship analysis of inhibitor of pyrrolotriazine skeleton and scoring function evaluation research.Building pharmacophore study: based on the TGF?R?-BMS22 crystal structure,the A02 pharmacophore model was constructed containing two hydrogen bond receptor(HBA)and four characteristics of hydrophobic(HYD);Based on the active compounds reported in previous studies,the pharmacophore model B10 was also yielded with two aromatic ring center(RA)and two hydrophobic(HYD)characteristics.Comparing two pharmacophore models and effective elements,the rational screening model was established : the first step through screening B10 pharmacophore model roughly,the second step through screeing A02 pharmacophore model carefully by Druglike Diverse Mini Maybridge,and ZINC Drug-Like database.Finally getting the potential activity of 2 new skeleton structure,compound YXY01-04 was designed,and combined with Lipinski's rule,ADMET properties and toxicological properties prediction,it was confirmed that compound YXY01-03 had novel structure,good drug-like properties,and potential activity.Compared with compound BMS22,compound YXY01-03 may have higher safety,which are worthy of further study.The screening based on scoring function is sensitive which is up to receptor,so we evaluated and verified the two docking methods of Lib Dock and CDOCKER and 11 scoring functions in Discovery Studio software.To further improve the reliability of virtual screening of TGF?? receptor inhibitors.Lib Dock and CDOCKER were conducted on a test including 24 TGF?? protein-ligand complexes respectively.Based on the root mean square deviation(RMSD)value(measured in ?)between the docking posture and the eutectic conformation as A reference,the docking success rate was 88%.A data of 281 known active ligands and 8677 inactive ligands was used to determine optimal scoring function(ROC curve receiver operating characteristic curves were used to compare scoring function).The results showed that the scoring function of LUDI1,PMF,LUDI 2,LUDI3,PMF04,PLP1,PLP2,Lig Score2,Jain and Lig Score1 was better than that of the random distribution model,and the AUC was 0.864,0.856,0.842,0.812,0.776,0.774,0.769,0.762,0.697 and 0.660.Based on the paired comparison of ROC curves,LUDI 1and PMF were selected as the best scoring function for virtual screening of TGF?? inhibitors.Further enrichment factor(EF)analysis also supported PMF and LUDI1 as the two optimal scoring functions.In addition,in order to better clarify the TGF?? receptor inhibitor of the relationship between structure and activity,in this study pyrrolotriazine skeleton inhibitors structure-activity relationship are analyzed to help us structural modification or reconstruction.and in such inhibitors based on the study of the structure-activity,we build the new TGF??inhibitor CQMU1901-1905 by structural modification and reconstruction.