Identification of Possible Glyoxalase II Inhibitors as Anticancer Agents by a Customized 3D Structure-Based Pharmacophore Model
Nizar A. Al‐Shar’i, Mohammad A. Hassan, Qosay Ali Al-Balas · Jordan Journal of Pharmaceutical Sciences · 2015
The glyoxalase system (which consists of glyoxalase-I and glyoxalase-II) is a ubiquitous metabolic pathway involved in cellular detoxification of the cytotoxic 2-oxoaldehydes. Tumour cells have high metabolic activity which results in increased cellular levels of such toxic metabolites. Therefore, tumour cells respond to this increase by increasing the activity 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 as potential anticancer drugs based on computer aided drug design. In this study, a customized 3D structure-based pharmacophore 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 generated pharmacophore to aid the search for selective glyoxalase-II inhibitors through virtual screening of small-molecules databases. Retrieved hits were extensively filtered then docked into the binding site of the enzyme. In order to maximize the chances of finding potential inhibitors of glyoxalase-II, docked hits were rescored using different scoring functions and consensually scored. Ten of the top ranked hits were selected as potential glyoxalase-II inhibitors.