Identification of the first "two digit nano-molar" inhibitors of the human glyoxalase-I enzyme as potential anticancer agents.

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 to eradicate cancer. OBJECTIVE Based on our previously 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 literature with two digits nano-molar activity. METHODS Molecular docking and in vitro assay were performed to discover these inhibitors and explore the active site's binding pattern. A detailed SAR scheme was generated, which identifies the significant functionalities responsible for the observed activity. RESULTS Compound 1 with an IC50 of 16.5 nM exhibited the highest activity, catechol moiety as an essential zinc chelating functionality. It has been shown by using molecular modeling techniques that the catechol moiety is responsible for the chelation zinc atom at the active site, an essential feature for enzyme inhibition. CONCLUSION Catechol derivatives are successful zinc chelators in the Glo-I enzyme while showing exceptional activity against the enzyme to the nanomolar level.