Do enthalpy and entropy distinguish first in class from best in class?
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A drug molecule should bind to its target with high affinity and selectivity. Because the binding affinity is a combined function of the binding enthalpy and the binding entropy, extremely high affinity requires that both terms contribute favorably to binding. The binding enthalpy, however, is notoriously more difficult to optimize than the binding entropy, a fact that has resulted in thermodynamically unbalanced molecules that do not achieve optimal potency. In fact, with current technologies, the enthalpic optimization of drug candidates may take years and only appear in second-generation products. Within that context, it is not surprising that structure/activity relationships (SARs) that explicitly incorporate the interplay between enthalpy and entropy and accelerate the optimization process are being developed and gaining popularity.
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The nonpolar desolvation is favorable to binding and is related to the hydrophobic effect when transferring nonpolar molecular surface from bulk water to a nonpolar medium.
“The nonpolar desolvation, favorable to binding, is related to the hydrophobic effect when transferring nonpolar molecular surface from the bulk water to a medium that is nonpolar, as is the case of many protein binding cavities (Tanford, 1980; Williams and Bardsley, 1999; Freire, 2008).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Freire, 2008
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- Authors
- Freire, E.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Freire, Ernesto
- ORCID
- Freire, Ernesto
- Venue
- Drug Discovery Today
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 13
- Issue
- 19-20
- Pages
- 869-874
- ISSN
- 1359-6446 (ISSN-L)
- PMC
- PMC2581116
- OpenAlex
- W2090907772
- Cited by
- 491
- References
- 30
- Citations by year
- 2026: 19 · 2025: 18 · 2024: 15 · 2023: 13 · 2022: 13 · 2021: 21 · 2020: 25 · 2019: 28 · 2018: 32 · 2017: 28 · 2016: 28 · 2015: 43 · 2014: 27 · 2013: 45 · 2012: 36
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Discovery Today (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- National Institute of General Medical Sciences (P01GM056550, GM 56550, R01GM057144, GM 57144)
- Topics
- Physical Sciences › Chemistry › Physical and Theoretical Chemistry › thermodynamics and calorimetric analyses
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Interaction Studies and Fluorescence Analysis
- Keywords
- binding enthalpy, binding entropy, enthalpy-entropy compensation, structure-activity relationship, drug-likeness, binding affinity, drug selectivity, thermodynamic balance, medication optimization
- MeSH terms
- Animals, Pharmaceutical Preparations, Humans, Hydrogen Bonding, Ligands, Receptors, Drug, Thermodynamics, Drug Design, Entropy
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