Computational study of human melatonin receptors, MT-1 and MT-2

The development of compounds that preferentially bind to specific human Melatonin receptors (hMT₁ and hMT₂) is critical in the elucidation of the specific function of the hMT₁ and hMT₂ receptors in vivo. Using homology models of the G protein-coupled receptors hMT₁ and hMT₂, docking simulations were performed using known and novel melatonin ligands. Currently 49 ligands with known bioactivities for specific melatonin receptors. Several of these compounds were selected for the docking study, while others were used in the development of the docking protocol. We will elucidate key chemical characteristics for the binding of compounds to specific melatonin receptors. Conclusions and docking protocols will be discussed with attention given to the novel ligands designed with the aid of 4D-QSAR.; Through the use of Quantitative Structure-Activity Relationships (specifically 4D-QSAR) the proposed active conformation of ligands bound to the active site can be determined. Elucidated from a previous 4D-QSAR study is the proposed alignment of the melatonin receptor ligands in the active site.; Using Comparative (Homology) Modelling human melatonin receptor models were constructed based on comparative and homology techniques. The models were then energy minimized and evaluated for statistical correctness.; The Simulated Docking of melatonin and nine melatonin-like ligands to hMT₁ and hMT₂ was performed using AutoDock 3.0.5. Following the simulated docking the results were imported into MOE for further analysis. The proposed docked structures were then minimized, including side chains of the binding site, and Interaction Energies and Binding Free Energies calculated.; Also included are mini-reviews about each of the methods employed.