Protein conformational flexibility modulates kinetics and thermodynamics of drug binding

• Autor(a) principal: Amaral, Marta
• Data de Publicação: 2017
• Outros Autores: Kokh, D. B., Bomke, J., Wegener, A., Buchstaller, H. P., Eggenweiler, H. M., Matias, P., Sirrenberg, C., Wade, R. C., Frech, M.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: https://doi.org/10.1038/s41467-017-02258-w
• topic: Chemistry(all); Biochemistry, Genetics and Molecular Biology(all); Physics and Astronomy(all)

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.