Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping |
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Institution: | 1. Department of Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan;2. Sleep Apnea Center, Kyushu University Hospital, Fukuoka, Japan;3. Department of Cardiovascular Medicine, Saiseikai Futsukaichi Hospital, Fukuoka, Japan;4. Clinical Physiological Laboratory, Saiseikai Futsukaichi Hospital, Fukuoka, Japan;1. Department of Physics and Chemistry, University of Palermo, Via Archirafi 36, I-90123 Palermo, Italy;2. Laboratoire des Solides Irradiés, CNRS-UMR 7642, CEA-DSM-IRAMIS, Ecole Polytechnique, Université Paris-Saclay, 91128 Palaiseau Cedex, France |
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Abstract: | An aminoquinazoline series targeting the essential bacterial enzyme GlmU (uridyltransferase) were previously reported (Biochem. J. 2012, 446, 405). In this study, we further explored SAR through a combination of traditional medicinal chemistry and structure-based drug design, resulting in a novel scaffold (benzamide) with selectivity against protein kinases. Virtual screening identified fragments that could be fused into the core scaffold, exploiting additional binding interactions and thus improving potency. These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding. Despite these significant improvements no significant antibacterial activity was yet observed within this class. |
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Keywords: | GlmU Aminoquinazoline Cell wall biosynthesis Uridyltransferase Virtual screening |
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