6EY9

Estimation of relative drug-target residence times by random acceleration molecular dynamics simulation

6EY9 の概要

• エントリーDOI: 10.2210/pdb6ey9/pdb
• 分子名称: Heat shock protein HSP 90-alpha, SULFATE ION, ~{N}-[(4-chlorophenyl)methyl]-~{N}-methyl-3-[(3-methylphenyl)methyl]-6-oxidanyl-1~{H}-indazole-5-carboxamide, ... (4 entities in total)
• 機能のキーワード: chaperone protein, atp binding, 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: 27117.74

構造登録者

Musil, D.,Lehmann, M.,Buchstaller, H.-P. (登録日: 2017-11-11, 公開日: 2018-05-30, 最終更新日: 2024-05-08)

主引用文献

Kokh, D.B.,Amaral, M.,Bomke, J.,Gradler, U.,Musil, D.,Buchstaller, H.P.,Dreyer, M.K.,Frech, M.,Lowinski, M.,Vallee, F.,Bianciotto, M.,Rak, A.,Wade, R.C.
Estimation of Drug-Target Residence Times by tau-Random Acceleration Molecular Dynamics Simulations.
J Chem Theory Comput, 14:3859-3869, 2018

PubMed Abstract: Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compounds and less than 2.0τ within congeneric series. Analysis of dissociation trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.

PubMed: 29768913
DOI: 10.1021/acs.jctc.8b00230

実験手法

X-RAY DIFFRACTION (2 Å)