Article abstract
Nature Chemical Biology 5, 358 - 364 (2009)
Published online: 22 March 2009 | doi:10.1038/nchembio.155
Molecular docking and ligand specificity in fragment-based inhibitor discovery
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 
-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 -lactamase, AmpC, which is unusual among -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 -lactamase.
- Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
Correspondence to: Brian K Shoichet1 e-mail: shoichet@cgl.ucsf.edu
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