Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking.

The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 µM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 µM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.

Identification of Dual-Target Compounds with Antifungal and Anti-NLRP3 Inflammasome Activity.

Invasive and superficial infections caused by the Candida species result in significant global morbidity and mortality. As the pathogenicity of these organisms is intimately intertwined with host immune response, therapies to target both the fungus and host inflammation may be warranted. Structural similarities exist between established inhibitors of the NLRP3 inflammasome and those of fungal acetohydroxyacid synthase (AHAS). Therefore, we leveraged this information to conduct an in silico molecular docking screen to find novel polypharmacologic inhibitors of these targets that resulted in the identification of 12 candidate molecules. Of these, compound 10 significantly attenuated activation of the NLPR3 inflammasome by LPS + ATP, while also demonstrating growth inhibitory activity against C. albicans that was alleviated in the presence of exogenous branched chain amino acids, consistent with targeting of fungal AHAS. SAR studies delineated an essential molecular scaffold required for dual activity. Ultimately, 10 and its analog 10a resulted in IC50 (IL-1ß release) and MIC50 (fungal growth) values with low µM potency against several Candida species. Collectively, this work demonstrates promising potential of dual-target approaches for improved management of fungal infections.