Discovery of new MurA inhibitors using induced-fit simulation and docking |
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| Affiliation: | 1. Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia;2. National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia;3. Group Bacterial Cell Envelopes and Antibiotics, Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ Paris Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette Cedex, France;4. Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia;1. Department of Chemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt;2. Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt;3. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University for Sustainable Development, Cairo, Egypt;4. Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;5. Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, Cairo, Egypt;1. Chemistry of Natural Compounds Department, Pharmaceutical Industries Research Division, National Research Center, 33 El Bohouth St. (former El Tahrir St.), Dokki, Giza, P.O. Box 12622, Egypt;2. Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Research Division, National Research Center, 33 El Bohouth St. (former El Tahrir St.), Dokki, Giza, P.O. Box 12622, Egypt;3. Green Chemistry Department, Chemical Industries Research Division, National Research Center, 33 El Bohouth St.(former El Tahrir St.), Dokki, Giza, P.O. Box 12622, Egypt;4. Department of Pharmaceutical Sciences, Massachusetts College of Pharmacy and Health Sciences, Boston, MA, USA;1. Infectious Diseases, Clinical Microbiology and Preventive Medicine Clinical Unit, Hospital Universitario Virgen del Rocío, Seville, Spain;2. Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain;3. Microbiology Department, University of Seville, Seville, Spain;1. Department of Basic Pharmaceutical Sciences, Faculty of Pharmacy, Cukurova University, Adana, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey;3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gaziosmanpasa University, Tokat, Turkey;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey;6. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Cukurova University, Adana, Turkey;7. Department of Analytical Chemistry, Faculty of Pharmacy, Cukurova University, Adana, Turkey;8. Van Yüzüncü Yıl University, Faculty of Veterinary Medicine, Department of Pharmacology and Toxicology, Van, Turkey |
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| Abstract: | We report on the successful application of ProBiS-CHARMMing web server in the discovery of new inhibitors of MurA, an enzyme that catalyzes the first committed cytoplasmic step of bacterial peptidoglycan synthesis. The available crystal structures of Escherichia coli MurA in the Protein Data Bank have binding sites whose small volume does not permit the docking of drug-like molecules. To prepare the binding site for docking, the ProBiS-CHARMMing web server was used to simulate the induced-fit effect upon ligand binding to MurA, resulting in a larger, more holo-like binding site. The docking of a filtered ZINC compound library to this enlarged binding site was then performed and resulted in three compounds with promising inhibitory potencies against MurA. Compound 1 displayed significant inhibitory potency with IC50 value of 1 μM. All three compounds have novel chemical structures, which could be used for further optimization of small-molecule MurA inhibitors. |
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| Keywords: | MurA inhibitors ProBiS-CHARMMing web server Induced fit Small-molecule inhibitors Antibacterial agents |
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