5fnd

Dynamic Undocking and the Quasi-Bound State as tools for Drug Design

spinqualitylabelsall models 5fnd, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5fnd is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: IQ5, SO4 Related: 5fnc, 5fnf Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. Publication Abstract from PubMed There is a pressing need for new technologies that improve the efficacy and efficiency of drug discovery. Structure-based methods have contributed towards this goal but they focus on predicting the binding affinity of protein-ligand complexes, which is notoriously difficult. We adopt an alternative approach that evaluates structural, rather than thermodynamic, stability. As bioactive molecules present a static binding mode, we devised dynamic undocking (DUck), a fast computational method to calculate the work necessary to reach a quasi-bound state at which the ligand has just broken the most important native contact with the receptor. This non-equilibrium property is surprisingly effective in virtual screening because true ligands form more-resilient interactions than decoys. Notably, DUck is orthogonal to docking and other 'thermodynamic' methods. We demonstrate the potential of the docking-undocking combination in a fragment screening against the molecular chaperone and oncology target Hsp90, for which we obtain novel chemotypes and a hit rate that approaches 40%. Dynamic undocking and the quasi-bound state as tools for drug discovery.,Ruiz-Carmona S, Schmidtke P, Luque FJ, Baker L, Matassova N, Davis B, Roughley S, Murray J, Hubbard R, Barril X Nat Chem. 2017 Mar;9(3):201-206. doi: 10.1038/nchem.2660. Epub 2016 Nov 14. PMID:28221352 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Heat Shock Protein structures

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