title: Highly predictive ligand-based pharmacophore and homology models of ABHD6.
abstract: α/β-Hydrolase domain-containing 6 (ABHD6) represents a potentially attractive therapeutic target for indirectly potentiating 2-arachidonoylglycerol signaling; however, the enzyme is currently largely uncharacterized. Here, we describe a five element, ligand-based pharmacophore model along with a refined homology model of ABHD6. Following a virtual screen of a modest database, both the pharmacophore and homology models were found to be highly predictive, preferentially identifying ABHD6 inhibitors over drug-like non-inhibitors. The models yield insight into the features required for optimal ligand binding to ABHD6 and the atomic structure of the binding site. In combination, the two models should be very helpful not only in high-throughput virtual screening, but also in lead optimization, and will facilitate the development of novel, selective ABHD6 inhibitors as potential drugs.
authors.affiliation: Center for Drug Discovery, Northeastern University, Boston, MA 02115, USA. a.bowman@neu.edu
authors.forename: Anna L
authors.initials: AL
authors.lastname: Bowman
authors.forename: Alexandros
authors.initials: A
authors.lastname: Makriyannis
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012372:ROC Curve; D016415:Sequence Alignment
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; C540878:ABHD6 protein, human; D008994:Monoacylglycerol Lipases