Thermodynamics guided lead discovery and optimization

G. Ferenczy, György M. Keseru

Research output: Contribution to journalArticle

93 Citations (Scopus)

Abstract

The documented unfavorable changes of physicochemical properties during lead discovery and optimization prompted us to investigate the present practice of medicinal chemistry optimization from a thermodynamic perspective. Basic principles of binding thermodynamics suggest that discriminating between enthalpy-driven and entropy-driven optimizations could be beneficial. We hypothesize that entropy-driven optimizations might be responsible for the undesirable trend observed in physicochemical properties. Consequently, we suggest that enthalpy-driven optimizations are preferred because they provide better quality compounds. Monitoring binding thermodynamics during optimization programs initiated from thermodynamically characterized hits or leads, therefore, could improve the success of discovery programs. Here, we summarize common industry practices for tackling optimization challenges and review how the assessment of binding thermodynamics could support medicinal chemistry efforts. This review focuses on the thermodynamic basis of the unfavorable changes observed in physicochemical properties in lead discovery and optimization programs and suggests that monitoring binding thermodynamics could contribute to an improvement in the quality of compounds identified.

Original languageEnglish
Pages (from-to)919-932
Number of pages14
JournalDrug Discovery Today
Volume15
Issue number21-22
DOIs
Publication statusPublished - Nov 2010

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Thermodynamics
Pharmaceutical Chemistry
Entropy
Quality Improvement
Industry

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

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Thermodynamics guided lead discovery and optimization. / Ferenczy, G.; Keseru, György M.

In: Drug Discovery Today, Vol. 15, No. 21-22, 11.2010, p. 919-932.

Research output: Contribution to journalArticle

Ferenczy, G. ; Keseru, György M. / Thermodynamics guided lead discovery and optimization. In: Drug Discovery Today. 2010 ; Vol. 15, No. 21-22. pp. 919-932.
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