A combined use of global and local approaches in 3D-QSAR

A new methodology fur 3D-QSAR studies, based on the combined use of global and local approaches, is proposed. Information on the whole molecular elect rostatic potential distribution is obtained from a global approach and used to build global models, based on the grid weighted holistic invariant mole cular (C-WHIM) descriptors, as well as to define an alignment criterion for developing local models, Moreover, a new technique based on local correlat ion indexes is proposed to perform the variable reduction. Both the global and the local models are obtained by a variable selection genetic algorithm s technique. The methodology is applied to a benchmark steroid data set. Th e molecular electrostatic potential and the experimental binding affinity c onstants for the corticosteroid-binding globulin are used as variables. The QSAR models obtained compared with those obtained by the CoMFA method show higher predictive ability and give insight into the local molecular featur es that determine high binding affinity. (C) 2000 Elsevier Science B.V. All rights reserved.