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

Martin Spichty , Antoine Taly , Franz Hagn , Horst Kessler , Sofia Barluenga , Nicolas Winssinger , Martin Karplus

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 N provides an additional evaluation criteria. As a last 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.

Mots clés: heat shock protein; macrolide; enhanced sampling; flexible ligand docking; postdocking analysis; binding mode evaluation; drug design

Martin Spichty, Antoine Taly, Franz Hagn, Horst Kessler, Sofia Barluenga, et al.. The HSP90 binding mode of a radicicol-like -oxime from docking, binding free energy estimations, and NMR N chemical shifts. Biophysical Chemistry, 2009, 143 (3), pp.111. ⟨10.1016/j.bpc.2009.04.003⟩. ⟨hal-00545277⟩