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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-SSS-L (10))
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Hillery, Paul
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Rutgers University
Schools of Arts and Sciences
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Pandit, Deepangi; Roosma, William; Misra, Milind et al. (2011) Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent. J Mol Model 17:181-200
Pandit, Deepangi; Fiorentino, Anna; Bindra, Supreet et al. (2011) Singular value decomposition analysis of the torsional angles of dopamine reuptake inhibitor GBR 12909 analogs: effect of force field and charges. J Mol Model 17:1343-51
Misra, Milind; Shi, Qing; Ye, Xiaocong et al. (2010) Quantitative structure-activity relationship studies of threo-methylphenidate analogs. Bioorg Med Chem 18:7221-38
Gilbert, Kathleen M; Boos, Terrence L; Dersch, Christina M et al. (2007) DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods. Bioorg Med Chem 15:1146-59
Banerjee, Amit; Misra, Milind; Pai, Deepa et al. (2007) Feature extraction using molecular planes for fuzzy relational clustering of a flexible dopamine reuptake inhibitor. J Chem Inf Model 47:2216-27
Fiorentino, Anna; Pandit, Deepangi; Gilbert, Kathleen M et al. (2006) Singular value decomposition of torsional angles of analogs of the dopamine reuptake inhibitor GBR 12909. J Comput Chem 27:609-20
Gilbert, Kathleen M; Venanzi, Carol A (2006) Hierarchical clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs. J Comput Aided Mol Des 20:209-25