The formation of epinephrine (adrenaline) from norepinephrine is catalyzed by the enzyme Phenylethanolamine N-methyltransferase (PNMT). Specific PNMT inhibitors that are active within the central nervous system (CNS) are of significant therapeutic importance. In the present study free energy calculations on a set of tetrahydroisoquinoline1 have been performed with the aim of developing a free energy (FE) based virtual screening protocol for the inhibitors of PNMT. FE calculations were used to compute the difference in binding free energy between various pairs of inhibitors in water and in PNMT using thermodynamic integration (TI) method with GROMOS53A62 force field and GROMOS962 program. The ligand topologies were generated using Automated Topology Builder (ATB)3 and edited manually. TI-FE calculations in water and protein show high degree of convergence in ns time scale. Also the study provides a robust means to distinguish the enatiomers binding to PNMT with the crucial structure activity relationship (SAR) for design of PNMT inhibitors. The work provides a stringent test of the ability of the GROMOS 53A62 force field to predict both the location of the inhibitor in the PNMT binding pocket and the relative binding free energy for a diverse set of ligands.
|Publication status||Published - 2010|
|Event||6th Annual SCMB Research Students Symposium - University of Queensland, Brisbane, Australia|
Duration: 1 Nov 2010 → 1 Nov 2010
Conference number: 6
|Conference||6th Annual SCMB Research Students Symposium|
|Period||1/11/10 → 1/11/10|