Ligand-supported homology modeling of the human melanin concentrating hormone receptor 1 (MCH-R1)

COMP 240

Mohamed Helal, masaad@olemiss.edu, Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677-1848 and MItchell A. Avery, mavery, Dept of Medicinal Chemistry, Univrsity of Mississippi, School of Pharmacy, University, MS 38677.
Melanin concentrating hormone (MCH) is a cyclic peptide secreted mainly in the hypothalamus. It is involved in the control of energy homeostasis, feeding behavior and body weight. Many studies have proved that administration of MCH-R1 antagonists significantly reduces food intake and causes weight loss in animal models. In this study, a homology model of the human MCH-R1 was constructed based on the crystal structure of bovine rhodopsin (PDB: 1u19). It was observed that MCH-R1 can bind ligands with high chemical diversity. To address this problem, the initial model was subjected to an extensive ligand-supported refinement using antagonists of different chemotypes. The refinement protocol involved several rounds of energy minimizations and molecular dynamics simulations. The refined model is able to explain the binding mode of MCH-R1 antagonists with diverse chemical structures. Moreover, it reveals new insights into the critical recognition sites within the receptor.
 

Poster Session
6:00 PM-8:00 PM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- Ballroom A, Poster

Division of Computers in Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009