Unraveling Potential Glyoxalase-I Inhibitors Utilizing Structure-Based Drug Design Techniques

Abstract

Mohammad H Fetian, Qosay A Al-Balas Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanCorrespondence: Qosay A Al-Balas, Department of Medicinal Chemistry & Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan, Tel [phone], Fax [phone], Email [email protected]: Glyoxalase system detoxifies methylglyoxal and other ketoaldehydes to produce innocuous metabolites that allow the cells to function normally. Its inhibition in cancer cells causes these toxic metabolites to accumulate, and the cancer cells enter the apoptotic stage.Methods: The techniques of Computer-Aided Drug Design (CADD) were used, and the compounds possessing a zinc-binding group from commercial databases were extracted, using the pharmacophore search protocol. These compounds were subjected to robust docking using the CDOCKER protocol within the Discovery Studio. Docking was performed on both Glo-I twin active sites. The biological activities of candidate hits were assessed using an in vitro assay against Glo-I.Results: Compounds containing zinc-binding groups were extracted from ASINEX® commercial database, which contains (91,001 compounds). This step has helped to retrieve 1809 ligands, which then were prepared and docked at the two active sites of Glo-I. The fourteen compounds, which have showed the highest scores in docking and returned acceptable Total Binding Energy values, were purchased and tested against the enzyme in vitro. Two compounds out of the fourteen, which were selected in the final step, possess tetrazole ring as zinc chelating moiety, and have showed moderate activity with an IC50 of 48.18μM for SYN 25285236 and 48.77 μM for SYN 22881895.Conclusion: Two hits with moderate activity are identified as the lead compounds against Glo-I. Both compounds possess a negatively ionized tetrazole ring as the zinc-binding moiety. These compounds will lead to the development of inhibitors with improved activities. Keywords: Glo-I, CDOCKER, zinc-binding group, tetrazole ring, structure-based drug design

Keywords

• glo-i
• cdocker
• zinc binding group
• tetrazole ring
• structure-based drug design.