5FNC

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

5FNC の概要

• エントリーDOI: 10.2210/pdb5fnc/pdb
• 関連するPDBエントリー: 5FND 5FNF
• 分子名称: HEAT SHOCK PROTEIN, HSP90-ALPHA, 6-CHLORO-4-N-[(4-METHYLPHENYL)METHYL]PYRIMIDINE- 2,4-DIAMINE, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: hsp90, drug design, chaperone, oncology
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27138.67

構造登録者

Ruiz-Carmona, S.,Schmidtke, P.,Luque, F.J.,Baker, L.M.,Matassova, N.,Davis, B.,Roughley, S.,Murray, J.,Hubbard, R.,Barril, X. (登録日: 2015-11-13, 公開日: 2016-11-23, 最終更新日: 2024-01-10)

主引用文献

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

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: 28221352
DOI: 10.1038/nchem.2660

実験手法

X-RAY DIFFRACTION (2.2 Å)