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 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.