Discovery of hydroxytriazole as a potential glyoxalase-I inhibitor utilizing computer-aided drug design techniques

The glyoxalase system, particularly Glyoxalase-I (Glo-I), plays a crucial role in detoxifying aldehyde metabolites into lactic acid. Inhibiting this enzyme causes the buildup of the poisonous aldehyde, leading to programmed cell death. In this study, molecular modelling techniques were employed, including high-throughput virtual screening (HTVS), followed by filtration procedures such as Lipinski's rule of five and Veber's rules, and finally CDOCKER docking, to prioritize compounds from the commercial Maybridge database. Sixteen compounds were carefully chosen and purchased from the Maybridge database for further experimental evaluation. The integrated computational and experimental workflow successfully culminated in the identification of a novel, potent Glyoxalase-I (Glo-I) inhibitor. One molecule has been discovered to inhibit Glo-I with an IC₅₀ of 11.1 µM. An analysis of the molecular dynamics of the active ligand (SPB07393SC) reveals stable behaviour. Crucially, this molecule incorporates a unique hydroxy triazole moiety, representing the first reported instance of this zinc-coordinating group in a Glo-I inhibitor. This will be utilized for the purpose of developing novel compounds with enhanced activity following appropriate modifications.

Cancer; Computer-aided drug design; Glyoxalase-I; Metalloenzyme; Molecular docking; Molecular dynamics; Virtual screening; Zinc-binding moiety.