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 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-lac

SUBMITTER: Chen Y 

PROVIDER: S-EPMC4006998 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature