CoMFA and CoMSIA 3D QSAR analysis on N1-arylsulfonylindole compounds as 5-HT6 antagonists

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series of N-1-arylsulfonylindole compounds as 5-HT6 antagonists. Evaluation of 20 compounds served to establish the models. The lowest energy conformer of compound I obtained from random search was used as template for alignment. The best predictions were obtained with CoMFA standard model (q(2) = 0.643, r(2) = 0.939) and with CoMSIA combined steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields (q(2) = 0.584, r(2) = 0.902). Both the models were validated by an external test set of eight compounds giving satisfactory predictive r(2) values of 0.604 and 0.654, respectively. The information obtained from CoMFA and CoMSIA 3D contour maps can be used for further design of specific 5-HT6 antagonists. (C) 2004 Elsevier Ltd. All rights reserved.