How are fragments optimized? A retrospective analysis of 145 fragment optimizations

G. Ferenczy, György M. Keseru

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Fragment optimizations in nearly 150 fragment-based drug discovery programs reported in the literature during the past fifteen years were investigated. By analyzing physicochemical properties and ligand efficiency indices we found that biochemical detection methods yield hits with superior ligand efficiency and lipophilicity indices than do X-ray and NMR. These advantageous properties are partially preserved in the optimization since higher affinity starting points allow optimizations better balanced between affinity and physicochemical property improvements. Size independent ligand efficiency (SILE) and lipophilic indices (primarily LELP) were found to be appropriate metrics to monitor optimizations. Small and medium enterprises (SME) produce optimized compounds with better properties than do big pharma companies and universities. It appears that the use of target structural information is a major reason behind this finding. Structure-based optimization was also found to dominate successful fragment optimizations that result in clinical candidates. These observations provide optimization guidelines for fragment-based drug discovery programs.

Original languageEnglish
Pages (from-to)2478-2486
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number6
DOIs
Publication statusPublished - Mar 28 2013

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Drug Discovery
Ligands
X-Rays
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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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How are fragments optimized? A retrospective analysis of 145 fragment optimizations. / Ferenczy, G.; Keseru, György M.

In: Journal of Medicinal Chemistry, Vol. 56, No. 6, 28.03.2013, p. 2478-2486.

Research output: Contribution to journalArticle

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