Design, Synthesis and Biological Evaluation of Potential Novel Zinc Binders Targeting Human Glyoxalase-I; A Validated Target for Cancer Treatment

Qosay Ali Al-Balas, Nizar Al-Shar'i, Katreen Banisalman, Mohammad Hassan, Ghazi Al Jabal, Ammar Almaaytah


The concept of using glyoxalase-I (Glo-I) enzyme inhibitors as anticancer agents is now becoming well-recognized due
to the important role the enzyme plays in the detoxification of cytotoxic aldehydes such as methylglyoxal (MG) to
harmless substances. In this study, a series of potential Glo-I inhibitor candidates possessing a zinc binding group were
synthesized based on structure-based design using Discovery Studio (DS) 3.5 from Biovia. LibDock protocol was used
to dock the compounds onto the active site of Glo-I. N-substituted aminobenzamide scaffolds were chosen, and 14
compounds were synthesized, fully characterized and tested in vitro against the target enzyme. A strong positive
correlation was noticed between in silico and experimental data. The top ranked compound (compound 14), which was
also the most active experimentally, showed 75.9% inhibition at a 50 μM concentration.


Computer Aided Drug Design; Glyoxalase-I; Zinc Binding Group; Anticancer, N-substituted aminobenzamide

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