title: Novel glyoxalase-I inhibitors possessing a "zinc-binding feature" as potential anticancer agents.
abstract: BACKGROUND
  The glyoxalase system including two thiol-dependent enzymes, glyoxalase I (Glo-I) and glyoxalase II, plays an important role in a ubiquitous metabolic pathway involved in cellular detoxification of cytotoxic 2-oxoaldehydes. Tumor cells have high glycolytic activity, leading to increased cellular levels of these toxic metabolites. The increased activity of the detoxification system in cancerous cells makes this pathway a viable target for developing novel anticancer agents. In this study, we examined the potential utility of non-glutathione-based inhibitors of the Glo-I enzyme as novel anticancer drugs.
  
  
  METHODS
  Computer-aided drug design techniques, such as customized pharmacophoric features, virtual screening, and flexible docking, were used to achieve the project goals. Retrieved hits were extensively filtered and subsequently docked into the active site of the enzyme. The biological activities of retrieved hits were assessed using an in vitro assay against Glo-I.
  
  
  RESULTS
  Since Glo-I is a zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was used to search for selective inhibitors via virtual screening of a small-molecule database. Seven hits were selected, purchased, and biologically evaluated. Three of the seven hits inhibited Glo-I activity, the most effective of which exerted 76.4% inhibition at a concentration of 25 µM.
  
  
  CONCLUSIONS
  We successfully identified a potential Glo-I inhibitor that can serve as a lead compound for further optimization. Moreover, our in silico and experimental results were highly correlated. Hence, the docking protocol adopted in this study may be efficiently employed in future optimization steps.
authors: Department of Medicinal Chemistry and Pharmacognosy.
authors: Qosay A
authors: QA
authors: Al-Balas
authors: Department of Medicinal Chemistry and Pharmacognosy.
authors: Mohammad A
authors: MA
authors: Hassan
authors: Department of Medicinal Chemistry and Pharmacognosy.
authors: Nizar A
authors: NA
authors: Al-Shar'i
authors: Department of Clinical Pharmacy.
authors: Nizar M
authors: NM
authors: Mhaidat
authors: Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
authors: Ammar M
authors: AM
authors: Almaaytah
authors: Department of Medicinal Chemistry and Pharmacognosy.
authors: Fatima M
authors: FM
authors: Al-Mahasneh
authors: Department of Medicinal Chemistry and Pharmacognosy.
authors: Israa H
authors: IH
authors: Isawi
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000597196:GLO1 protein, human; D007791:Lactoylglutathione Lyase
keywords: Discovery Studio 3.5; cancer; flexible docking; glyoxalase-I; ketol; zinc-binding feature