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Title

The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts

Authors
Spichty, Martin
Taly, Antoine
Hagn, Franz
Kessler, Horst
Barluenga, Sofia
Karplus, Martin
Published in Biophysical Chemistry. 2009, vol. 143, no. 3, p. 111-123
Abstract We determine the binding mode of a macrocyclic radicicol-like oxime to yeast HSP90 by combining computer simulations and experimental measurements. We sample the macrocyclic scaffold of the unbound ligand by parallel tempering simulations and dock the most populated conformations to yeast HSP90. Docking poses are then evaluated by the use of binding free energy estimations with the linear interaction energy method. Comparison of QM/MM-calculated NMR chemical shifts with experimental shift data for a selective subset of backbone 15N provides an additional evaluation criteria. As a final test we check the binding modes against available structure–activity-relationships. We find that the most likely binding mode of the oxime to yeast HSP90 is very similar to the known structure of the radicicol–HSP90 complex.
Keywords Heat shock proteinMacrolideEnhanced samplingFlexible ligand dockingBinding mode evaluationIn silico drug design
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SPICHTY, Martin et al. The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts. In: Biophysical Chemistry, 2009, vol. 143, n° 3, p. 111-123. https://archive-ouverte.unige.ch/unige:24719

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Deposited on : 2012-12-18

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