The influence of lead discovery strategies on the properties of drug candidates

Nat Rev Drug Discov. 2009 Mar;8(3):203-12. doi: 10.1038/nrd2796.


Despite the widespread acceptance of guidelines related to desirable physicochemical properties of potential small-molecule drugs, key properties - such as lipophilicity - of recently developed clinical candidates and advanced lead compounds have been shown to differ significantly from those of historical leads and drugs. By analysing the physicochemical properties of a large database of hits and corresponding leads identified in the past decade, we show that this undesirable phenomenon can be traced back to the nature of high-throughput screening hits and hit-to-lead optimization practices. Conceptual and organizational adjustments may be required to enable a smooth lead-evolution process that reduces the chance of high compound-related attrition in clinical trials.

Publication types

  • Review

MeSH terms

  • Chemistry, Pharmaceutical
  • Clinical Trials as Topic
  • Databases, Factual
  • Drug Discovery*
  • Drug Industry / organization & administration*
  • Guidelines as Topic
  • Humans
  • Pharmaceutical Preparations / chemistry*


  • Pharmaceutical Preparations