Relationship Among Ligand Conformations in Solution, in the Solid State, and at the Hsp90 Binding Site: Geldanamycin and Radicicol

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• 作者：Pahk Thepchatri ; Tomasso Eliseo ; Daniel O. Cicero ; David Myles ; and ; James P. Snyder
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：March 21, 2007
• 年：2007
• 卷：129
• 期：11
• 页码：3127 - 3134
• 全文大小：214K
• 年卷期：v.129,no.11(March 21, 2007)
• ISSN：1520-5126

文摘

The unknown effects of a receptor's environment on a ligand's conformation presents a difficultchallenge in predicting feasible bioactive conformations, particularly if the receptor is ill-defined. The primaryhypothesis of this work is that a structure's conformational ensemble in solution presents viable candidatesfor protein binding. The experimental solution profile can be achieved with the NAMFIS (NMR analysis ofmolecular flexibility in solution) method, which deconvolutes the average NMR spectrum of small flexiblemolecules into individual contributing conformations with varying populations. Geldanamycin and radicicolare structurally different macrocycles determined by X-ray crystallography to bind to a common site on thecellular chaperone heat shock protein 90 (Hsp90). Without benefit of a receptor structure, NAMFIS hasidentified 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 proteinswith GLIDE followed by MM-GBSA scoring reproduces the experimental crystallographic binding poses.