A carregar...
Publicação
Protein conformational flexibility modulates kinetics and thermodynamics of drug binding
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 2.58 MB | Adobe PDF |
Orientador(es)
Resumo(s)
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.
Descrição
Palavras-chave
General Chemistry General Biochemistry,Genetics and Molecular Biology General Physics and Astronomy