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Nat Biotechnol. 2007 Jan;25(1):71-5.

Structure-based maximal affinity model predicts small-molecule druggability.

Author information

  • 1Department of Molecular Informatics, Research Technology Center, Pfizer Global Research & Development, Cambridge, Massachusetts 02139, USA. alan.cheng@amgen.com

Abstract

Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.

PMID:
17211405
DOI:
10.1038/nbt1273
[PubMed - indexed for MEDLINE]
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