Molecular docking and ligand specificity in fragment-based inhibitor discovery

• Published in: Nature chemical biology Vol. 5; no. 5; pp. 358 - 364
• Main Authors: Shoichet, Brian K, Chen, Yu
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.05.2009; Nature Publishing Group
• Subjects: Antibiotics; beta-Lactamase Inhibitors; Binding Sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Crystal structure; Crystallography, X-Ray; Drug Discovery; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Inhibitors; Ligands; Models, Molecular; Molecular biology; Molecular Structure; Pharmaceutical sciences
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.155

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.