Abstract
Fragment screens have successfully identified new scaffolds in drug discovery, often with relatively high hit rates (5%) using small screening libraries (1,000–10,000 compounds). This raises two questions: would other noteworthy chemotypes be found were one to screen all commercially available fragments (>300,000), and does the success rate imply low specificity of fragments? We used molecular docking to screen large libraries of fragments against CTX-M β-lactamase. We identified ten millimolar-range inhibitors from the 69 compounds tested. The docking poses corresponded closely to the crystallographic structures subsequently determined. Notably, these initial low-affinity hits showed little specificity between CTX-M and an unrelated β-lactamase, AmpC, which is unusual among β-lactamase inhibitors. This is consistent with the idea that the high hit rates among fragments correlate to a low initial specificity. As the inhibitors were progressed, both specificity and affinity rose together, yielding to our knowledge the first micromolar-range noncovalent inhibitors against a class A β-lactamase.
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Acknowledgements
This work was supported by US National Institutes of Health grants GM63813 and GM59957 (to B.K.S.). We thank D.G. Teotico (University of California, San Francisco) for providing the AmpC inhibitors and for insightful discussions, and J. Hert and C. Laggner for assistance with similarity search. We thank D.G. Teotico, S. Boyce, M. Mysinger and J. Irwin for reading the manuscript. We also thank R. Bonnet.
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This project was designed by Y.C. and B.K.S. together; all the experiments were undertaken by Y.C. Both authors contributed to interpreting the results and writing the paper.
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Chen, Y., Shoichet, B. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nat Chem Biol 5, 358–364 (2009). https://doi.org/10.1038/nchembio.155
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DOI: https://doi.org/10.1038/nchembio.155
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