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Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

Authors Al-Balas Q, Hassan M, Al-Shar’i N, Mhaidat N, Almaaytah A, Al-Mahasneh F, Isawi I

Received 20 April 2016

Accepted for publication 23 May 2016

Published 17 August 2016 Volume 2016:10 Pages 2623—2629

DOI https://doi.org/10.2147/DDDT.S110997

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Wei Duan


Qosay A Al-Balas,1 Mohammad A Hassan,1 Nizar A Al-Shar’i,1 Nizar M Mhaidat,2 Ammar M Almaaytah,3 Fatima M Al-Mahasneh,1 Israa H Isawi1

1Department of Medicinal Chemistry and Pharmacognosy, 2Department of Clinical Pharmacy, 3Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan


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.
Conclusion: 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.

Keywords: cancer, glyoxalase-I, zinc-binding feature, flexible docking, Discovery Studio 3.5, ketol

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