5LO0

HSP90 WITH indazole derivative

5LO0 の概要

• エントリーDOI: 10.2210/pdb5lo0/pdb
• 関連するPDBエントリー: 4EEH
• 分子名称: Heat shock protein HSP 90-alpha, [2-azanyl-6-[4,5-bis(fluoranyl)-2-(4-methylpiperazin-1-yl)sulfonyl-phenyl]quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone (3 entities in total)
• 機能のキーワード: chaperone
• 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: 26278.43

構造登録者

Graedler, U.,Amaral, M.,Schuetz, D. (登録日: 2016-08-08, 公開日: 2017-11-29, 最終更新日: 2024-01-10)

主引用文献

Schuetz, D.A.,Richter, L.,Amaral, M.,Grandits, M.,Gradler, U.,Musil, D.,Buchstaller, H.P.,Eggenweiler, H.M.,Frech, M.,Ecker, G.F.
Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors.
J. Med. Chem., 61:4397-4411, 2018

PubMed Abstract: Residence time and more recently the association rate constant k are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant k decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization.

PubMed: 29701469
DOI: 10.1021/acs.jmedchem.8b00080

実験手法

X-RAY DIFFRACTION (2.3 Å)