title: Cholesteryl ester transfer protein inhibitors in coronary heart disease: Validated comparative QSAR modeling of N, N-disubstituted trifluoro-3-amino-2-propanols.
abstract: Cholesteryl ester transfer protein (CETP) converts high density lipoprotein cholesterol to low density lipoproteins. It is a promising target for treatment of coronary heart disease. Two dimensional quantitative structure activity relationship (2D-QSAR), hologram QSAR (HQSAR) studies and comparative molecular field analysis (CoMFA) as well as comparative molecular similarity analysis (CoMSIA) were performed on 104 CETP inhibitors. The statistical qualities of generated models were justified by internal and external validation, i.e., q(2) and R(2)pred respectively. The best 2D-QSAR model was obtained with q(2) and R(2)pred values of 0.794 and 0.796 respectively. The 2D-QSAR study suggests that unsaturation, branching and van der Waals volumes may play important roles. The HQSAR model showed q(2) and R(2)pred values of 0.628 and 0.550 respectively. Similarly, CoMFA model showed q(2) and R(2)pred values of 0.707 and 0.755 respectively whereas CoMSIA model was obtained with q(2) and R(2)pred values of 0.696 and 0.703 respectively. CoMFA and CoMSIA studies indicate that steric factors are important at substituted phenoxy and tetrafluoroethoxy groups whereas electropositive factors play important role at difluoromethyl group. The results of 3D-QSAR studies validate those of 2D-QSAR and HQSAR studies as well as the earlier observed SAR data. Current work may help to develop better CETP inhibitors.
authors.affiliation: Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, P.O. Box-17020, Jadavpur University, Kolkata 700032, India.
authors.forename: Chanchal
authors.initials: C
authors.lastname: Mondal
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Halder
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Adhikari
authors.forename: Tarun
authors.initials: T
authors.lastname: Jha
mesh_terms: D000465:Algorithms; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016000:Cluster Analysis; D003327:Coronary Disease / Q000188:drug therapy; D055808:Drug Discovery; D006801:Humans; D016018:Least-Squares Analysis; D016014:Linear Models; D008958:Models, Molecular; D020005:Propanols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: C506642:CETP protein, human; D002317:Cardiovascular Agents; D053480:Cholesterol Ester Transfer Proteins; D020005:Propanols
keywords: Cholesteryl ester transfer protein; CoMFA; CoMSIA; Coronary heart disease; HQSAR; Validation