6ELO

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

Summary for 6ELO

• Entry DOI: 10.2210/pdb6elo/pdb
• Descriptor: Heat shock protein HSP 90-alpha, 4-ethyl-6-[4-(2-fluorophenyl)-3-methyl-1~{H}-pyrazol-5-yl]benzene-1,3-diol (3 entities in total)
• Functional Keywords: chaperone protein, atp binding, chaperone
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 26914.11

Authors

Musil, D.,Lehmann, M.,Eggenweiler, H.-M. (deposition date: 2017-09-29, release date: 2018-05-30, Last modification date: 2024-05-08)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)