The long range goal of the proposed research is to use techniques of computational chemistry and pharmacophore modeling to help medicinal chemists design drugs useful in the treatment of cocaine abuse. In particular, structure-function data for analogs of GBR 12909 will be modeled in an attempt to determine the molecular features of a pharmacophore for optimal binding at the dopamine transporter (DAT) and optimal selectivity for the DAT versus the serotonin transporter (SERT).
The Specific Aims of the research are: (1) to evaluate several multivaraiate and cluster analysis techniques in order to find the optimal method of classify, compare, and identify representative conformations of these highly flexible molecules, and (2) to use representative conformations in a Comparative Molecular Field Analysis study in order to investigate the hypothesis of a common DAT binding pharmacophore for the GBR analogs and the structurally very different DAT inhibitor, methylphenidate. The work is carried out in collaboration with Dr. Kenner Rice, NIH, whose group will synthesize the analogs, Dr. Richard Rothman, NIH, whose group will test their DAT and SERT activity, and Dr. Rajesh Dav?, New Jersey Institute of Technology, who will provide expertise in clustering techniques. The significance of this work is that it is the first pharmacophore modeling study of GBR analogs that takes into account the complexities of their conformational potential energy surface.
