ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Modelling of ORL1 receptor-ligand interactions

Milan Senćanski, Milovan D. Ivanović, and Ljiljana Došen-Mićović

Innovation Centre of the Faculty of Chemistry, Serbia University of Belgrade, Studentski trg 12-16, P.O. Box 51, 11158, Belgrade, Serbia

E-mail: lmicovic@chem.bg.ac.rs

Abstract: An opioid receptor like (ORL1) receptor is one of a family of G-protein-coupled receptors (GPCR); it represents a new pharmaceutical target with extensive therapeutic potential for the regulation of important biological functions such as nociception, mood disorders, drug abuse, learning or cardiovascular control. Although the crystal structure of the inactive form of the ORL1 receptor has been determined, little is known about its activation. By using X-ray structures of the β2-adrenegic receptor in its inactive (2RH1) and active (3P0G) states as templates, inactive and active homology models of the ORL1 receptor were constructed. Structurally diverse sets of strongly binding antagonists and agonists were docked with both ORL1 receptor forms. The major receptor-ligand interactions responsible for antagonist and agonist binding were identified. Although both sets of ligands, agonists and antagonists, bind to the same region of the receptor, they occupy partially different binding pockets. Agonists bind to the inactive receptor in a slightly different manner than antagonists. This difference is more pronounced in binding to the active ORL1 receptor model and points to the amino acids at the extracellular end of TM6, suggesting that this region is important for receptor-activation.

Keywords: molecular modelling – ORL1 receptor – ligand-receptor interactions – docking simulation – molecular dynamics

Full paper is available at www.springerlink.com.

DOI: 10.2478/s11696-014-0577-z

Chemical Papers 68 (10) 1305–1316 (2014)