Profiling The Interaction Mechanism Of MCHR1 Antagonists:An In Silico Method

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. While, after more than ten years of development, the study of MCHR1 antagonists has always stopped at the first phase of the clinical trial. Besides the traditional challenges in drug design such as absorption, distribution, metabolism and elimination (ADME) and safety profiles, further development of significant numbers of MCHR1 antagonists has been compromised by potential cardiac liabilities induced by human ether-a-go-go related gene (hERG) channel binding. So it’s of great significance to explore the binding mechanism of MCHR1 antagonists that are capable of overcoming hERG liabilities while remaining orally active, potent and selective.In the present work, a up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists were subjected to both ligand-and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with Q2=0.509, R2ncv=0.841 and R2pred=0.745. Moreover, the recently reported X-ray crystal structure of P-adrenergic receptor (PDB:2RH1) was utilized as template in homology modeling due to its high sequence similarity to MCHR1. In addition, docking studies and molecular dynamics (MD) simulations (receptor in water and lipid bilayer, respectively) were carried out for further elucidation of the binding modes of MCHR1 antagonists.To sum up, our main findings are:(1) The 3D-QSAR model obtained has good internal and external predictive ability. (2) MD analysis shows similar results to those obtained in docking study. (3) The interaction forces in the binding site of MCHR1 include hydrophobic actions, an ionic interaction and H-bonds.All in all, the knowledge gained from our models we anticipate will facilitate the design and optimization of novel MCHR1 antagonists as promising anti-obesity agents.