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

Autor:	Amer E. Alkhalifa, Rand A. Al-Waqfi, Qosay Al-Balas, Nehad M. Ayoub, Mohammad A. Hassan, Nizar A. Al-Shar’i
Rok vydání:	2019
Předmět:	Antineoplastic Agents 01 natural sciences Structure-Activity Relationship chemistry.chemical_compound Lactoylglutathione lyase 0103 physical sciences Drug Discovery Humans Enzyme Inhibitors Physical and Theoretical Chemistry Binding site IC50 chemistry.chemical_classification Virtual screening Binding Sites Molecular Structure 010304 chemical physics biology Methylglyoxal Lactoylglutathione Lyase 0104 chemical sciences Computer Science Applications Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Enzyme chemistry Biochemistry biology.protein Pharmacophore Protein Binding Glyoxalase system
Zdroj:	Journal of Computer-Aided Molecular Design. 33:799-815
ISSN:	1573-4951 0920-654X
DOI:	10.1007/s10822-019-00226-8
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d0e82524a70ad2279c2c8d002d432249 https://doi.org/10.1007/s10822-019-00226-8 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.