Interaction mechanisms of a melatonergic inhibitor in the melatonin synthesis pathway

Acetylserotonin-O-methyltransferase (ASMT) catalyzes the conversion of nor-melatonin to melatonin. Different levels of melatonin have been employed as a trait marker for psychiatric conditions, for this reason ASMT is thought to be an ideal target for developing novel therapeutic agents for the treatment of several mood disorders. In current study, the structural and functional details of the ASMT-B22 complex have been studied using docking and molecular dynamics (MD) simulation. Molecular docking results illustrated that both hydrogen bonding interactions as well as hydrophobic interactions made significant contributions for ligand binding and Arg210 appeared to be the anchor amino acid for the recognition of the receptor. Two hundred nanoseconds MD simulations using AMBER12 were performed to explore the behavior of the ASMT-B22 complex in aqueous solution, focusing on the structural changes induced as a result of inhibitor binding. From root mean square deviation, it was observed that the N-terminal residues endured a conformational change at 11th and 20th ns time scale. The root mean square fluctuation showed high motional flexibility at N-terminal residues because of structural alterations whereas the active site region comprising of a loop was comparatively stable and showed low fluctuations. Radial distribution functions calculated on the major interacting residues of the pocket revealed strengthening of the ASMT-B22 complex indicating the increase in the hydrogen bond interactions. Axial frequency distribution analysis is applied on trajectories for a vivid explanation of hydrogen bonding patterns. Results yielded will be useful in the design of more potent inhibitors of ASMT for normalizing the melatonin levels.