ReviewAnnual review of biophysics2013
Entropy-enthalpy compensation: role and ramifications in biomolecular ligand recognition and design.
Review in Annual review of biophysics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 193 papers.
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193 citing papers in PubMed.
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- Activation parameters, enthalpy-entropy compensation and the temperature-dependent activity of enzymes.Protein science : a publication of the Protein Society · 2026Article
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- Thermodynamic Data Remain a Hot Tip for Decoding Binding Affinity and Water Impact on Protein-Ligand Complex Formation to Assist Lead Optimization.Journal of medicinal chemistry · 2026Review
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- Deciphering Mutational Impacts on c-Src-HK2 Interaction in Colorectal Cancer Progression, and Identification of Potential Phytocompounds Inhibitors: A Molecular Simulation and Free Energy Calculation Approach.Current medicinal chemistry · 2026Article
- Microsecond simulations to investigate the structural mechanism of super-resistant double mutations in BTK to the covalent inhibitor ibrutinib in multiple leukemia.Scientific reports · 2025Article
- Activation parameters, enthalpy-entropy compensation and the temperature-dependent activity of enzymes.bioRxiv : the preprint server for biology · 2025Article
- Chiral macrocycles forming high-affinity host-guest homoternary complexes for chiral discrimination and amplified circularly polarized luminescence.Nature communications · 2025Article
- Thermodynamics of Molecular Transport Through a Nanochannel: Evidence of Energy-Entropy Compensation.International journal of molecular sciences · 2025Article
- Article
133 more citing papers are in PubMed but not listed here.
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Abstract
Recent calorimetric studies of interactions between small molecules and biomolecular targets have generated renewed interest in the phenomenon of entropy-enthalpy compensation. In these studies, entropic and enthalpic contributions to binding are observed to vary substantially and in an opposing manner as the ligand or protein is modified, whereas the binding free energy varies little. In severe examples, engineered enthalpic gains can lead to completely compensating entropic penalties, frustrating ligand design. Here, we examine the evidence for compensation, as well as its potential origins, prevalence, severity, and ramifications for ligand engineering. We find the evidence for severe compensation to be weak in light of the large magnitude of and correlation between errors in experimental measurements of entropic and enthalpic contributions to binding, though a limited form of compensation may be common. Given the difficulty of predicting or measuring entropic and enthalpic changes to useful precision, or using this information in design, we recommend ligand engineering efforts instead focus on computational and experimental methodologies to directly assess changes in binding free energy.
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