title: Pharmacophore modeling and virtual screening studies to design potential COMT inhibitors as new leads.
abstract: 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 for its implications in numerous neurological disorders like Parkinson's disease (PD), schizophrenia, and depression. The COMT gene is associated with many allelic variants, the Val108Met polymorphism being the most clinically significant. Availability of crystal structure of both 108V and 108M forms of human soluble-COMT (S-COMT) facilitated us to use structure-based virtual screening approach to obtain new hits by screening a library of CNS permeable compounds from ZINC database. In this study, E-pharmacophore was also used to generate pharmacophore models based on a series of known COMT inhibitors. A five-point pharmacophore model consisting of one hydrogen-bond acceptor (A), two hydrogen bond donors (D), and two aromatic rings (R) was generated for both the polymorphic forms of COMT. These models were then used for filtering ZINC-CNS permeable library to obtain new hits. Physicochemical properties were also calculated for all the hits obtained from both the approaches for favorable ADME properties. These identified hits maybe of interest for further structural optimization and biological evaluation assays.
authors.affiliation: Bioinformatics Infrastructure Facility, Sri Venkateswara College (University of Delhi), Benito Juarez Road, Dhaula Kuan, New Delhi, India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jatana
authors.forename: Aditya
authors.initials: A
authors.lastname: Sharma
authors.forename: N
authors.initials: N
authors.lastname: Latha
mesh_terms: D001665:Binding Sites; D002394:Catechol O-Methyltransferase / Q000737:chemistry*; D003198:Computer Simulation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D002394:Catechol O-Methyltransferase