Thermodynamics guided lead discovery and optimization

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...

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Bibliographic Details
Published inDrug discovery today Vol. 15; no. 21; pp. 919 - 932
Main Authors Ferenczy, György G., Keserű, György M.
Format Journal Article
LanguageEnglish
Published Kidlington Elsevier Ltd 01.11.2010
Elsevier
Subjects
Biological and medical sciences
Calorimetry
Chemical Phenomena
Drug Discovery
Entropy
General pharmacology
Medical sciences
Molecular Weight
Pharmaceutical technology. Pharmaceutical industry
Pharmacology. Drug treatments
Protein Binding
Proteins - chemistry
Proteins - metabolism
Structure-Activity Relationship
Thermodynamics
Thermodynamics
Pharmaceutical technology
Optimization
Research and development
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Summary: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.
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ISSN:1359-6446
1878-5832
DOI:10.1016/j.drudis.2010.08.013