Molecular modeling of human MT1 and MT2 melatonin receptors

Malfunction of G-protein coupled receptors (GPCR) provokes large amount of diseases. Their adequate treatment requires rational design of new high affinity and high selectivity drugs targeting these receptors. Molecular modeling represents a powerful tool to solve the problem. In this work, we present three-dimensional models of human MT, and MT, melatonin receptors, members of the GPCR family. The models were based on the X-ray structure of bovine rhodopsin. The modeling approach employs an original computational procedure for optimization of receptor-ligand structures. It includes rotation of one of transmembrane a-helices around its axis with simultaneous assessment of the quality of complexes according to a number of developed criteria. The optimal geometry of the receptor-ligand binding was selected based on analysis of complementarity of hydrophobic/hydrophilic properties between the ligand and its protein environment in the binding site. The resulting 'optimized' models were applied to inspect the details of protein-ligand interactions for melatonin and a number of its analogs with known affinities for MT, and MT, receptors. The results permit rationalization of experimental data on affinities and selectivities of studied compounds towards both receptor subtypes. Prospects of the constructed models in drug design are discussed.