2D and 3D QSAR models for identifying diphenylpyridylethanamine based inhibitors against cholesteryl ester transfer protein.
Cholesteryl ester transfer protein (CETP) inhibitors hold promise as new agents against coronary heart disease. Molecular modeling techniques such as 2D-QSAR and 3D-QSAR analysis were applied to establish models to distinguish potent and weak CETP inhibitors. 2D and 3D QSAR models-based a series of diphenylpyridylethanamine (DPPE) derivatives (newly identified as CETP inhibitors) were then performed to elucidate structural and physicochemical requirements for higher CETP inhibitory activity. The linear and spline 2D-QSAR models were developed through multiple linear regression (MLR) and support vector machine (SVM) methods. The best 2D-QSAR model obtained by SVM gave a high predictive ability (R(2)train=0.929, R(2)test=0.826, Q(2)LOO=0.780). Also, the 2D-QSAR models uncovered that SlogP_VSA0, E_sol and Vsurf_DW23 were important features in defining activity. In addition, the best 3D-QSAR model presented higher predictive ability (R(2)train=0.958, R(2)test=0.852, Q(2)LOO=0.734) based on comparative molecular field analysis (CoMFA). Meanwhile, the derived contour maps from 3D-QSAR model revealed the significant structural features (steric and electronic effects) required for improving CETP inhibitory activity. Consequently, twelve newly designed DPPE derivatives were proposed to be robust and potent CETP inhibitors. Overall, these derived models may help to design novel DPPE derivatives with better CETP inhibitory activity.
College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, Fujian, China. Electronic address: chenmeimei1984@163.com.
Meimei
M
Chen
College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, Fujian, China.
Xuemei
X
Yang
College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, Fujian, China.
Xinmei
X
Lai
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, China.
Yuxing
Y
Gao
D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D010627:Phenethylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D013329:Structure-Activity Relationship
D053480:Cholesterol Ester Transfer Proteins; D010627:Phenethylamines; D011725:Pyridines
CETP; Diphenylpyridylethanamine derivatives; MLR; QSAR; SVM