Selection of Bioactive Conformations and Alignment Rules by 4way PLS Analysis

Validation using external data

Abstract

Comparative molecular field analysis (CoMFA) has been widely used in 3D QSAR studies. Although CoMFA is a general method, there are some critical problems in the practical usage. A major problem of CoMFA and most other 3D QSAR methodologies is that the results are dependent on the chosen bioactive conformations and the corresponding alignment rules of molecules. Recently, we have proposed a novel method with a 3-way PLS formulation for solving the conformation/alignment problem [K.Hasegawa, M.Arakawa and K.Funatsu, Chemometrics Intell. Lab. Syst., 50, 253-261 (2000)]. In this study, we extended the previous method to investigate conformation and alignment independently. The possible 3D conformations of all molecules were generated by conformational analysis and they were characterized by field variables of CoMFA. Then 4way array for 4way PLS analysis was created by similarity criterion, and conformations largely contributing to inhibitory activity were selected. To demonstrate the general utility, the data set of Benzodiazepine analogue inhibitors of Cholecystokinin was used as a test sample. Furthermore, validation using external data was carried out to prove the usefulness of selection method of conformations and alignment rules by 4wayPLS method proposed in this study.