Molecular docking and ligand specificity in fragment-based inhibitor discovery

By Yu Chen, Brian K. Shoichet. 2009

254 citations recorded by the source corpus.

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.

Subfields: Computational Theory and Mathematics, Molecular Medicine, Pharmacology

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Citations in the corpus

Challenges and advances in computational docking: 2009 in review (2011, background): “Thus, Shoichet and co-workers (105,106) set out to address this apparent paradox and investigate the relevant questions: can docking prioritize fragments and predict their binding modes?”
Key Topics in Molecular Docking for Drug Design (2019, methodology): “In a study developed by Chen and Shoichet, a fragment-based approach was used as an alternative to a lead-like virtual screen campaign, obtaining increased hit rates for β-Lactamase inhibitors, and ultimately yielding hits in the low μM range [157].”
In silico methods and tools for drug discovery (2021, background): “By contrast, fragment-based docking approaches detect fragments with a reasonable affinity that is generally low compared to entire ligand structures [177].”
Ligand Pose and Orientational Sampling in Molecular Docking (2013, background): “Ever more frequently, docking predictions are tested by subsequent xray crystallographic structures, often confirming the predicted geometries of the docked complex [7, 14, [59] [60] [61] [62] [63] [64] [65] .”