Int. J. Mol. Sci. 2013, 14, 8093-8121; doi:10.3390/ijms14048093 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Homology Models of Melatonin Receptors: Challenges and Recent Advances Daniele Pala 1, Alessio Lodola 1, Annalida Bedini 2, Gilberto Spadoni 2 and Silvia Rivara 1,* 1 Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy; E-Mails:
[email protected] (D.P.);
[email protected] (A.L.) 2 Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, I-61029 Urbino, Italy; E-Mails:
[email protected] (A.B.);
[email protected] (G.S.) * Author to whom correspondence should be addressed; E-Mail:
[email protected]; Tel.: +39-0521-905-061; Fax: +39-0521-905-006. Received: 7 March 2013; in revised form: 28 March 2013 / Accepted: 28 March 2013 / Published: 12 April 2013 Abstract: Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models.