ArticleJournal of the American Chemical Society2010
Protein flexibility and conformational entropy in ligand design targeting the carbohydrate recognition domain of galectin-3.
Article in Journal of the American Chemical Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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Who cites it
86 citing papers in PubMed, 229 citations in OpenAlex.
- DT-TRAP enables accurate target recognition via simplified dosing and low-temperature incubation.Journal of pharmaceutical analysis · 2026Article
- Developing Galectin-3-Targeted Therapeutics in Diseases: Three Distinct Galectin-3 Segments for Targeting.Expert reviews in molecular medicine · 2026Review
- The Power of Protein Dynamics in Binding and Allostery.Biochemistry · 2026Review
- Article
- Quantitative Structure-Activity Relationships for Human Galectin-3 Inhibitors: Insights from Quantum Chemical Interaction Energy Terms.Journal of chemical information and modeling · 2025Article
- Article
- Computer-aided molecular design and optimization of potent inhibitors disrupting APC‒Asef interaction.Acta pharmaceutica Sinica. B · 2024Article
- Article
- Ligand-induced protein transition state stabilization switches the binding pathway from conformational selection to induced fit.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Ligand Sulfur Oxidation State Progressively Alters Galectin-3-Ligand Complex Conformations To Induce Affinity-Influencing Hydrogen Bonds.Journal of medicinal chemistry · 2023Article
- Discovery ofACS medicinal chemistry letters · 2023Article
- Relaxation and single site multiple mutations to identify and control allosteric networks.Methods (San Diego, Calif.) · 2023Review
- Exploring multivalent carbohydrate-protein interactions by NMR.Chemical Society reviews · 2023Review
- Article
- Temperature as a modulator of allosteric motions and crosstalk in mesophilic and thermophilic enzymes.Frontiers in molecular biosciences · 2023Review
- Protein dynamics: The future is bright and complicated!Structural dynamics (Melville, N.Y.) · 2023Article
- What is the Sugar Code?Chembiochem : a European journal of chemical biology · 2022Review
- Design and synthesis of novel 3-triazolyl-1-thiogalactosides as galectin-1, -3 and -8 inhibitors.RSC advances · 2022Article
- Article
26 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.