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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Identification of the First “Two Digit Nano-molar” Inhibitors of the Human Glyoxalase-I Enzyme as Potential Anticancer Agents

Author(s): Qosay A. Al‑Balas*, Mahmoud A. Al-Sha'er, Mohammad A. Hassan and Esra’a Al Zou’bi

Volume 18, Issue 4, 2022

Page: [473 - 483] Pages: 11

DOI: 10.2174/1573406417666210714170403

Price: $65

Abstract

Background: Glyoxalase-I (Glo-I) enzyme is recognized as an indispensable druggable target in cancer treatment. Its inhibition will lead to the accumulation of toxic aldehyde metabolites and cell death. Paramount efforts were spent to discover potential competitive inhibitors with the aim to eradicate cancer.

Objective: Based on our previous work on this target for discovering potent inhibitors of this enzyme, herein, we address the discovery of the most potent Glo-I inhibitors reported in the literature with two digits nano-molar activity.

Methods: Molecular docking and in vitro assay were performed to discover these inhibitors and explore the binding pattern within the active site. A detailed SAR scheme was generated, which identifies the major functionalities responsible for the observed activity.

Results: Compound 1 with an IC50 of 16.5 nM exhibited the highest activity, which possess catechol moiety as an essential zinc chelating functionality. It has been shown by using molecular modeling techniques that the catechol moiety is responsible for chelation zinc atom at the active site; an essential feature for enzyme inhibition.

Conclusion: Catechol derivatives are successful zinc chelators in Glo-I enzyme while showing exceptional activity against the enzyme to nanomolar level.

Keywords: Glyoxalase-I, anticancer, catechol derivatives, two digit nanomolar inhibitor, NCI database, aldehyde metabolites.

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Graphical Abstract

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