F1-2025. Novel DNA Gyrase Inhibitors: Structure-guided Discovery and Optimization of Pyrrolamides
Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: An NMR screening approach was used to identify new chemical starting points for inhibitors of bacterial DNA gyrase. Further elaboration of these fragments, guided by computational design and X-ray crystallography resulted in the discovery of the pyrrolamides, a novel series of potent DNA gyrase inhibitors. Methods: A library of low molecular weight “fragments” was screened by NMR for binding to the B subunit of DNA gyrase (GyrB), resulting in the identification of several promising hits (including 1). Computational docking and X-ray crystallography were used to extend this fragment into compounds such as 2. Inhibition of the Staphylococcus aureus DNA gyrase ATPase activity was used to monitor potency improvements. Results: NMR screening resulted in the identification of a fragment hit (1) with a Kd of 160 μM against GyrB. Iterative structure-based approaches subsequently converted 1 into the pyrrolamide series of potent inhibitors with submicromolar IC50 values against S. aureus DNA gyrase (70 nM for 2). Conclusions: Fragment screening identified pyrrole derivatives that bound to GyrB. Computational docking and X-ray crystallography guided the extension of these initial fragments into potent inhibitors of DNA gyrase that advanced a lead series for further optimization.
Dave Timms1, Grant Walkup2, Haihong Ni2, Neil Hales1, Oluyinka Green3, Alex Breeze1, Alok Singh4, Ann Eakin, PhD5 and  O. Green, None., (1)AstraZeneca, (2)AstraZeneca R&D Boston, (3)AstraZeneca R&D Boston, Waltham, MA, (4)Astrazeneca, (5)Infection Discovery, Cancer and Infection Research Area, AstraZeneca R&D Boston


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