title: The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts.
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 (15)N 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.
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, Université de Strasbourg, 8 allé Gaspard Monge, Strasbourg, France. mspichty@isis-ulp.org
authors.forename: Martin
authors.initials: M
authors.lastname: Spichty
authors.forename: Antoine
authors.initials: A
authors.lastname: Taly
authors.forename: Franz
authors.initials: F
authors.lastname: Hagn
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Sofia
authors.initials: S
authors.lastname: Barluenga
authors.forename: Nicolas
authors.initials: N
authors.lastname: Winssinger
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
mesh_terms: D003198:Computer Simulation; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry*; D018942:Macrolides / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D009587:Nitrogen Isotopes; D010091:Oximes / Q000737:chemistry*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D018841:HSP90 Heat-Shock Proteins; D018942:Macrolides; D009587:Nitrogen Isotopes; D010091:Oximes; C035359:monorden