ABSTRACT
The glyoxalase system [which consists of glyoxalase-I and glyoxalase-II] is a ubiquitous metabolic pathway involvedin cellular detoxification of the cytotoxic 2-oxoaldehydes. Tumour cells have high metabolic activity which results inincreased cellular levels of such toxic metabolites. Therefore, tumour cells respond to this increase by increasing theactivity of the detoxifying glyoxalase system which makes it a viable target for the development of anticancer drugs.This work represents the first study that aims to find none-glutathione-based inhibitors of the glyoxalase-II enzyme aspotential anticancer drugs based on computer aided drug design. In this study, a customized 3D structure-basedpharmacophore model was generated which is a hybrid of three complementary 3D pharmacophores. Since glyoxalase-II is a binuclear zinc metalloenzyme, a customized Zn-binding pharmacophoric feature was added to the generatedpharmacophore to aid the search for selective glyoxalase-II inhibitors through virtual screening of small-moleculesdatabases. Retrieved hits were extensively filtered then docked into the binding site of the enzyme. In order tomaximize the chances of finding potential inhibitors of glyoxalase-II, docked hits were rescored using different scoringfunctions and consensually scored. Ten of the top ranked hits were selected as potential glyoxalase-II inhibitors