ArticleNature communications2017
Protein conformational flexibility modulates kinetics and thermodynamics of drug binding.
Article in Nature communications, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers.
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Who cites it
111 citing papers in PubMed.
- Computer-Aided Drug Design for Type 2 Diabetes-Related Enzymes: Polarizable and Nonpolarizable Simulations of Enzyme-Inhibitor Complexes.Journal of chemical information and modeling · 2026Article
- Fully Automatable Relative Binding Free Energy Calculations with Enhanced Sampling Using FAST/MBAR.Journal of chemical theory and computation · 2026Article
- DT-TRAP enables accurate target recognition via simplified dosing and low-temperature incubation.Journal of pharmaceutical analysis · 2026Article
- Impact of Time, Temperature, and Conformational Changes on the Characterization of Cardiotonic Steroid-NaThe Journal of membrane biology · 2026Review
- DeepPath: overcoming data scarcity for protein transition pathway prediction using physics-based deep learning.Chemical science · 2026Article
- Ligand-mediated conformation diversity of Hsp90 revealed by GaMD simulations and Markov model.Molecular diversity · 2026Article
- Hydrophobic interactions of a substrate with L193 on the flexible substrate-binding loop contribute to 3α-hydroxysteroid dehydrogenase/carbonyl reductase catalytic efficiency.Protein science : a publication of the Protein Society · 2026Article
- Bioinformatics and computational exploration of novel inhibitors targeting KRAS G12C mutant protein in lung adenocarcinoma.Discover oncology · 2026Article
- Ultrasonication-assisted green synthesis, in silico EGFR-binding analysis, and cytotoxic evaluation of nitro-perimidines for non-small cell lung cancer.Journal of computer-aided molecular design · 2026Article
- In Silico Analysis of CMolecules (Basel, Switzerland) · 2025Article
- Implementation of Replica-Averaged Restraints from Nuclear Magnetic Resonance Measurement with UNRES Coarse Grained Model of Polypeptide Chains.Molecules (Basel, Switzerland) · 2025Article
- Spatial charge-hydrophobicity configuration modulates cationic peptide transport in cartilage.Biophysical journal · 2025Article
- Enhancing antibody-antigen interaction prediction with atomic flexibility.PLoS computational biology · 2025Article
- Mechanistic insight into the dynamics of Mur ligase through a comprehensive timescale-specific approach.Communications chemistry · 2025Article
- Repurposed clindamycin suppresses pyroptosis in tumor-associated macrophages through Inhibition of caspase-1.Journal of experimental & clinical cancer research : CR · 2025Article
- Engineering functionally-optimized aptamers against SARS-Cov-2 for blocking spike-ACE2 interaction and aptasensor detection.Materials today. Bio · 2025Article
- Residence time in drug discovery: current insights and future perspectives.Pharmacological reports : PR · 2025Review
- Article
- Understanding the HIV-CA protein and the ligands that bind at the N-terminal domain (NTD) - C-terminal domain (CTD) interface.RSC medicinal chemistry · 2025Review
- Review
51 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Structure-based drug design has often been restricted by the rather static picture of protein-ligand complexes presented by crystal structures, despite the widely accepted importance of protein flexibility in biomolecular recognition. Here we report a detailed experimental and computational study of the drug target, human heat shock protein 90, to explore the contribution of protein dynamics to the binding thermodynamics and kinetics of drug-like compounds. We observe that their binding properties depend on whether the protein has a loop or a helical conformation in the binding site of the ligand-bound state. Compounds bound to the helical conformation display slow association and dissociation rates, high-affinity and high cellular efficacy, and predominantly entropically driven binding. An important entropic contribution comes from the greater flexibility of the helical relative to the loop conformation in the ligand-bound state. This unusual mechanism suggests increasing target flexibility in the bound state by ligand design as a new strategy for drug discovery.
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