Identification through structure-based methods of a bacterial NAD+-dependent DNA ligase inhibitor that avoids known resistance mutations |
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| Affiliation: | 1. Department of Chemistry, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States;2. Department of Bioscience, Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Dr., Waltham, MA 02451, United States;1. Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg D. Obradovića 3, 21000 Novi Sad, Serbia;2. Oncology Institute of Vojvodina, Faculty of Medicine, University of Novi Sad, Institutski put 4, 21204 Sremska Kamenica, Serbia;3. Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljka 3, 21000 Novi Sad, Serbia;1. GVK Biosciences Private Limited, Medicinal Chemistry Division, 28A, IDA Nacharam, Hyderabad 500076, India;2. Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, India;1. School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, POB 1627, 70211 Kuopio, Finland;2. Departments of Pharmacology and Toxicology and Psychiatry, University of Toronto, Campbell Family Mental Health Research Institute, M5S 1A8 Toronto, Ontario, Canada |
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| Abstract: | In an attempt to identify novel inhibitors of NAD+-dependent DNA ligase (LigA) that are not affected by a known resistance mutation in the adenosine binding pocket, a detailed analysis of the binding sites of a variety of bacterial ligases was performed. This analysis revealed several similarities to the adenine binding region of kinases, which enabled a virtual screen of known kinase inhibitors. From this screen, a thienopyridine scaffold was identified that was shown to inhibit bacterial ligase. Further characterization through structure and enzymology revealed the compound was not affected by a previously disclosed resistance mutation in Streptococcus pneumoniae LigA, Leu75Phe. A subsequent medicinal chemistry program identified substitutions that resulted in an inhibitor with moderate activity across various Gram-positive bacterial LigA enzymes. |
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| Keywords: | Adenosine Thienopyridine Resistance Antibacterial |
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