title: Generation of the first structure-based pharmacophore model containing a selective "zinc binding group" feature to identify potential glyoxalase-1 inhibitors.
abstract: Within this study, a unique 3D structure-based pharmacophore model of the enzyme glyoxalase-1 (Glo-1) has been revealed. Glo-1 is considered a zinc metalloenzyme in which the inhibitor binding with zinc atom at the active site is crucial. To our knowledge, this is the first pharmacophore model that has a selective feature for a "zinc binding group" which has been customized within the structure-based pharmacophore model of Glo-1 to extract ligands that possess functional groups able to bind zinc atom solely from database screening. In addition, an extensive 2D similarity search using three diverse similarity techniques (Tanimoto, Dice, Cosine) has been performed over the commercially available "Zinc Clean Drug-Like Database" that contains around 10 million compounds to help find suitable inhibitors for this enzyme based on known inhibitors from the literature. The resultant hits were mapped over the structure based pharmacophore and the successful hits were further docked using three docking programs with different pose fitting and scoring techniques (GOLD, LibDock, CDOCKER). Nine candidates were suggested to be novel Glo-1 inhibitors containing the "zinc binding group" with the highest consensus scoring from docking.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. qabalas@just.edu.jo
authors.forename: Qosay
authors.initials: Q
authors.lastname: Al-Balas
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hassan
authors.forename: Buthina
authors.initials: B
authors.lastname: Al-Oudat
authors.forename: Hassan
authors.initials: H
authors.lastname: Alzoubi
authors.forename: Nizar
authors.initials: N
authors.lastname: Mhaidat
authors.forename: Ammar
authors.initials: A
authors.lastname: Almaaytah
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002352:Carrier Proteins / Q000138:chemical synthesis / Q000737:chemistry; D020134:Catalytic Domain; D016208:Databases, Factual; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors / Q000737:chemistry; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry*
chemical_list: D002352:Carrier Proteins; C017800:zinc-binding protein; D007791:Lactoylglutathione Lyase; D015032:Zinc