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Hongbin Yuan, Alan P. Kozikowski, and Pavel A. Petukhov*

CoMFA Study of Piperidine Analogues of Cocaine at the Dopamine Transporter: Exploring the Binding Mode of the 3  -Substituent of the Piperidine Ring Using Pharmacophore-Based Flexible Alignment. Hongbin Yuan, Alan P. Kozikowski, and Pavel A. Petukhov*

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Hongbin Yuan, Alan P. Kozikowski, and Pavel A. Petukhov*

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  1. CoMFA Study of Piperidine Analogues of Cocaine at the Dopamine Transporter: Exploring the Binding Mode of the 3-Substituent of the Piperidine Ring Using Pharmacophore-Based Flexible Alignment Hongbin Yuan, Alan P. Kozikowski, and Pavel A. Petukhov* Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago J. Med. Chem. 2004, 47, 6137-6143

  2. outline • Goal: to develop a model of the dopamine transporter (DAT) using QSAR analysis of cocaine analogues • No crystal structure of the DAT is available, but many piperidine analogues of cocaine have been synthesized and evaluated for binding affinity • A highly predictive model for the DAT would facilitate development of therapeutics for cocaine abuse • Methods • Training set of 36 compounds, test set of 6 compounds • Genetic Algorithm Similarity Program (GASP) used to generate pharmacophore by comparing known ligands for DAT • Comparative molecular field analysis (CoMFA) calculates steric and electrostatic field energies • Refined with Flexible Superposition (FlexS)

  3. Cocaine and analogues

  4. Flow chart training set

  5. Top two pharmacophores DS = H-bond donor AS = H-bond acceptor site AA = H-bond acceptor atom

  6. Quantitative predictions are accurate

  7. Conclusions • Two pharmacophore models suggest multiple binding modes for ligands • Good fit when QSAR applied to test set of 6 compounds • Predictive power for new potential therapeutics

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