Biomolecular docking is a frequent applied molecular modeling technique in order to predict preferred binding orientations of ligands in proteins [1]. In our research group we use experimental data guided docking approaches and common scaffold clustering for the unbiased prioritization of docking poses without relying on energetic scoring functions [2-4].Recently, we have applied this workflow to amphetamine derivatives in homology models of the serotonin and dopamine transporters. Final aim of the study is the elucidation of the mephedrone binding mode - an amphetamine analog with increasing reports of abuse.  We found equivalent binding modes for both transport proteins: One, where the ligands' orientation was perpendicular, another, where it was parallel to the membrane. Both poses might be part of a dynamic transition between two low-energy states during binding. Ongoing 3D-QSAR studies and mutational experiments, will help in further prioritization of one of the poses.[1] Lengauer T, Rarey M (1996) Computational methods for biomolecular docking. Curr. Opin. Struct. Biol. 6 (3): 402�406.[2] Sarker S, Weissensteiner R, Steiner I, Sitte HH, Ecker, GF, Freissmuth M, Sucic S (2010) The High-Affinity Binding Site for Tricyclic Antidepressants Resides in the Outer Vestibule of the Serotonin Transporter. Mol. Pharmacol. 78 (6) 1026-1035.[3] Klepsch F, Chiba P, Ecker GF (2011) Exhaustive Sampling of Docking Poses Reveals Binding Hypotheses for Propafenone Type Inhibitors of P-Glycoprotein. PLoS Comput Biol 7(5): e1002036. doi:10.1371/journal.pcbi.1002036[4] Richter L, de Graaf C, Sieghart W, Varagic Z, M�rzinger  M, de Esch IJP, Ecker GF, Ernst M (2012) Diazepam-bound GABAA receptor models identify new benzodiazepine binding-site ligands. Nat. Chem. Biol. Epub ahead of print. doi:10.1038/nchembio.917

Prioritization of docking poses in human serotonin and dopamine transporters by the use of common scaffold clustering

244th National Meeting (2012)

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