Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
| Autor: | Pedro M. Matias, Jörg Bomke, Daria B. Kokh, Rebecca C. Wade, Hans-Peter Buchstaller, C. Sirrenberg, Ansgar Wegener, Marta Amaral, Matthias Frech, H.-M. Eggenweiler |
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| Přispěvatelé: | Molecular, Structural and Cellular Microbiology (MOSTMICRO), Instituto de Tecnologia Química e Biológica António Xavier (ITQB) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Chemistry(all) Protein Conformation Science Entropy Kinetics General Physics and Astronomy Thermodynamics Molecular Dynamics Simulation Physics and Astronomy(all) Crystallography X-Ray Ligands Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Molecular dynamics Protein structure Humans HSP90 Heat-Shock Proteins Binding site lcsh:Science Binding Sites Multidisciplinary biology Chemistry Drug discovery Ligand Biochemistry Genetics and Molecular Biology(all) Protein dynamics General Chemistry Surface Plasmon Resonance 3. Good health 030104 developmental biology Drug Design Chaperone (protein) Mutagenesis Site-Directed biology.protein lcsh:Q Crystallization Protein Binding |
| Zdroj: | Nature Communications Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Nature Communications, Vol 8, Iss 1, Pp 1-14 (2017) |
| Popis: | 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. An understanding of the dynamics of drug binding and unbinding processes is important for drug discovery. Here, the authors give insights into the binding mechanism of small drug-like molecules to human Hsp90 by combining thermodynamics and kinetics studies as well as molecular dynamics simulations. |
| Databáze: | OpenAIRE |
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