title: Relationship among ligand conformations in solution, in the solid state, and at the Hsp90 binding site: geldanamycin and radicicol.
abstract: The unknown effects of a receptor's environment on a ligand's conformation presents a difficult challenge in predicting feasible bioactive conformations, particularly if the receptor is ill-defined. The primary hypothesis of this work is that a structure's conformational ensemble in solution presents viable candidates for protein binding. The experimental solution profile can be achieved with the NAMFIS (NMR analysis of molecular flexibility in solution) method, which deconvolutes the average NMR spectrum of small flexible molecules into individual contributing conformations with varying populations. Geldanamycin and radicicol are structurally different macrocycles determined by X-ray crystallography to bind to a common site on the cellular chaperone heat shock protein 90 (Hsp90). Without benefit of a receptor structure, NAMFIS has identified the bioactive conformers of geldanamycin and radicicol in CDCl3 solution with populations of 4% and 21%, respectively. Conversely, docking the set of NAMFIS conformers into the unliganded proteins with GLIDE followed by MM-GBSA scoring reproduces the experimental crystallographic binding poses.
authors.affiliation: Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Pahk
authors.initials: P
authors.lastname: Thepchatri
authors.forename: Tomasso
authors.initials: T
authors.lastname: Eliseo
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Cicero
authors.forename: David
authors.initials: D
authors.lastname: Myles
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
mesh_terms: D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011485:Protein Binding; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D008024:Ligands; D018942:Macrolides; D012996:Solutions; C035359:monorden; C001277:geldanamycin