3D-QSAR and docking studies on 2-arylbenzoxazole and linker-Y transthyretin amyloidogenesis inhibitors  

作　　者：ZHAO LiJun ZHANG LiangRen LEI Ming 

机构地区：[1]State Key Laboratory of Chemical Resource Engineering,Institute of Materia Medica,College of Science,Beijing University of Chemical Technology [2]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University

出　　处：《Science China Chemistry》2013年第11期1550-1563,共14页中国科学（化学英文版）

基　　金：supported by the National Natural Science Foundation of China(21072018);the Fundamental Research Funds for the Central Universities(ZY1213);the Foundation of State Key Laboratory of Natural and Biomimetic Drugs(K20120202)

摘　　要：Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.Transthyretin （TTR）, a plasma protein with a tetramer structure, could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer. These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR. A number of small molecules like 2-arylbenzoxazoles （ABZ） analogues are proposed as promising therapeutic strategy to treat amyloidosis. In this work, comparative molecular field analysis （CoM- FA） and comparative molecular similarity indices analysis （CoMSIA） three-dimensional quantitative structure-activity rela- tionship （3D-QSAR） and docking studies were performed on series of 2-arylbenzoxazoles （ABZ） and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level. Significant correlation coefficients for ABZ series （CoMFA, r^2 = 0.877, q^2 = 0.431; CoMSIA, r^2 = 0.836, q2 = 0.447） and those for linker-Y series （CoMFA, r^2 = 0.828, q^2 = 0.522; CoMSIA, r^2 = 0.800, q^2 = 0.493） were obtained, and the generated models were validated using test sets. In addition, docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR. These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.

关 键 词：TRANSTHYRETIN 3D-QSAR 2-arylbenzoxazoles linker-Y DOCKING binding mode 

分 类 号：TQ460.1[化学工程—制药化工]