Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Integrating CADD Methodologies for the Design of Novel COMT Inhibitors
Catechol-O-methyltransferase (COMT) catalyzes the methylation of catecholamines, including neurotransmitters like dopamine, epinephrine and norepinephrine, leading to their degradation. COMT has been a subject of study as it has implications in numerous neurological disorders like Parkinson's disease (PD), depression, schizophrenia and several mood disorders (1).
Availability of crystal structure of human soluble-COMT (S-COMT) (2) has helped us in modeling of membrane-bound COMT (MB-COMT) and thus paved the way for the discovery of a novel lead molecule using integrated computer aided drug design (CADD) methodologies (3-8). Combination of both structure-based (molecular docking, de novo ligand design) and ligand-based (QSAR, pharmacophore modeling) approaches that models separate facets of the natural system, will allow us to use all available information to screen a chemical database in a more objective and meaningful way.
In this study, we examine the structure of MB-COMT refined by molecular dynamics simulations. We have also conducted detailed computational modeling studies to understand the molecular mechanisms for the catalytic behavior of human MB-COMT with respect to AdoMet (the methyl donor) and various substrates. We have also carried out docking studies with known COMT inhibitors (5 ,9) to understand physico-chemical interactions in the protein-ligand complex in order to identify the optimal binding geometry. The virtual screening procedure has been implemented in a docking pipeline that performs a step-by-step, target specific, filtering approach for data reduction to discover inhibitors with novel scaffolds. We hope that the combination of energy terms from structure-based docking studies with the chemical knowledge of a ligand-based pharmacophore search will leverage the strengths of both approaches to produce a good diversity of active molecules. Results of these studies will be discussed and presented.
Bioinformatics Infrastructure Facility,