Rational choice of bioactive conformations through use of conformation analysis and 3-way partial least squares modeling

Comparative molecular field analysis (CoMFA) has become widely used in thre e-dimensional (3D) QSAR studies. Although CoMFA has been of general use, th ere are some critical problems in the proper application. A major problem o f CoMFA, including most other 3D QSAR methodologies, is that the results ar e dependent on the chosen bioactive conformations and the corresponding ali gnment rules of molecules. Recently, we have proposed a novel method with a 3-way PLS formulation for solving the conformation/alignment problem in 3D QSAR studies [K. Hasegawa, M. Arakawa, K. Funatsu, Chemom. Intell. Lab. Sy st., 47 (1999) 33-40]. The purpose of the present study is to demonstrate t he general utility of our approach by applying to a real CoMFA data set. Th e data set of Protein-Tyrosine Kinase (PTK) inhibitors was used as a test s ample. The possible 3D conformations of all molecules were generated by con formational analysis and they were characterized by field variables of CoMF A. To each unique conformation of the most active compound, one sample-vari able sheet comprising of the most similar conformations was defined. The 3- way arrays for 3-way PLS analysis were created by collecting all sample-var iable sheets. From the regression coefficient values of the 3-way PLS model , conformations largely contributing to inhibitory activity were selected a nd the resulting final CoMFA model could give the reasonable 3D coefficient contour maps. (C) 2000 Elsevier Science B.V. All rights reserved.