title: 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-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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D065093:beta-Lactamase Inhibitors
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D065093:beta-Lactamase Inhibitors