Format

Send to

Choose Destination
Nat Chem Biol. 2009 May;5(5):358-64. doi: 10.1038/nchembio.155. Epub 2009 Mar 22.

Molecular docking and ligand specificity in fragment-based inhibitor discovery.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.

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 beta-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 beta-lactamase, AmpC, which is unusual among beta-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 beta-lactamase.

PMID:
19305397
PMCID:
PMC4006998
DOI:
10.1038/nchembio.155
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Secondary source IDs, Grant support

Publication type

MeSH terms

Substances

Secondary source IDs

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center