The transient receptor potential vanilloid type 1 (TRPV1) plays a major role in pain perception. Therefore, the discovery of TRPV1 ligands as non-opioid analgesics is an area of therapeutic interest. Recently determined rat TRPV1 (rTRPV1) structures (PDB codes 3J5R, 3J5Q) allowed us the application of structure-based methods to the study of TRPV1 modulation.In a previous study, we identified three potent modulators of hTRPV1 using ligand-based pharmacophore modeling[1]. Here, we present the use of these experimentally validated pharmacophore models to identify the binding modes of both agonists and antagonists to the TRPV1.To this end, we performed docking with flexible side-chains of three known agonists (capsaicin, RTX, sRTX), 11 antagonists (capsazepine, 10 quinazolines) and three identified modulators to the experimental rTRPV1 structures.The ligand-based pharmacophore models provided an insight into the key structural features of TRPV1 modulation: a hydrophobic core with a donor-acceptor group placed at one side. Taking this into consideration, as well as the broad mutational data available in literature, we have selected the most prominent binding mode of highly active ligands of TRPV1. In both cases, agonists and antagonists are able to form a p-p stacking interaction with the aromatic moiety of the residue Tyr511 located in the lower part of the binding pocket and a hydrophobic one with the Met547 in the upper region. However, they exhibit a slightly different hydrogen bond network. Whereas agonists interact with the residues Tyr511, Ser512 and Glu570, antagonists form hydrogen bonds with Tyr511, Thr550 and Glu570.We acknowledge financial support provided by the Austrian Science Fund grant n�W1232Tsareva D., Ecker G., 245th ACS Meeting&Exposition, oral communication

Docking study of binding to TRPV1 structure: Agonists vs. antagonists

248th National Meeting (2014)

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