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J Med Chem. 2011 Feb 10;54(3):851-7. doi: 10.1021/jm101273e. Epub 2010 Dec 30.

A practical use of ligand efficiency indices out of the fragment-based approach: ligand efficiency-guided lead identification of soluble epoxide hydrolase inhibitors.

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Chemistry Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd. 3-1-98 Kasugade-naka, Konohana, Osaka 554-0022, Japan.


Ligand efficiency is frequently used to evaluate fragment compounds in fragment-based drug discovery. We applied ligand efficiency indices in a conventional virtual screening-initiated lead generation study of soluble epoxide hydrolase inhibitors. From a considerable number of screening hits, we carefully selected a compound exhibiting relatively weak inhibitory activity but high ligand efficiency. This ligand efficiency-guided selection could reveal compounds possessing preferable lead-like characteristics in terms of molecular size and lipophilicity. The following hit-to-lead medicinal chemistry campaign successfully led to a more potent, ADMET-clean, lead-like compound preserving high ligand efficiency. Retrospective analyses, including consideration of the more recently proposed indices of ligand efficiency, shed light on the validity of our hit triage and hit-to-lead studies. The present work proposes a practical methodology for lead generation using the concept of ligand efficiency.

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