5FNF
Dynamic Undocking and the Quasi-Bound State as tools for Drug Design
Summary for 5FNF
| Entry DOI | 10.2210/pdb5fnf/pdb |
| Related | 5FNC 5FND |
| Descriptor | HEAT SHOCK PROTEIN, HSP90-ALPHA, SULFATE ION, 4-[(E)-N-oxidanyl-C-pyridin-3-yl-carbonimidoyl]benzene-1,3-diol, ... (4 entities in total) |
| Functional Keywords | hsp90, drug design, chaperone, oncology |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 27024.12 |
| Authors | Ruiz-Carmona, S.,Schmidtke, P.,Luque, F.J.,Baker, L.M.,Matassova, N.,Davis, B.,Roughley, S.,Murray, J.,Hubbard, R.,Barril, X. (deposition date: 2015-11-13, release date: 2016-11-23, Last modification date: 2024-01-10) |
| Primary citation | Ruiz-Carmona, S.,Schmidtke, P.,Luque, F.J.,Baker, L.,Matassova, N.,Davis, B.,Roughley, S.,Murray, J.,Hubbard, R.,Barril, X. Dynamic undocking and the quasi-bound state as tools for drug discovery. Nat Chem, 9:201-206, 2017 Cited by PubMed Abstract: 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%. PubMed: 28221352DOI: 10.1038/nchem.2660 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.1 Å) |
Structure validation
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