Thepchatri Pahk, Eliseo Tomasso, Cicero Daniel O, Myles David, Snyder James P
Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA.
J Am Chem Soc. 2007 Mar 21;129(11):3127-34. doi: 10.1021/ja064863p. Epub 2007 Feb 27.
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.
受体环境对配体构象的未知影响给预测可行的生物活性构象带来了艰巨挑战，尤其是当受体定义不明确时。这项工作的主要假设是，溶液中一种结构的构象集合提供了蛋白质结合的可行候选构象。实验溶液谱可以通过NAMFIS（溶液中分子柔性的核磁共振分析）方法获得，该方法将小的柔性分子的平均核磁共振谱解卷积为具有不同丰度的各个贡献构象。格尔德霉素和雷迪西醇是结构不同的大环化合物，通过X射线晶体学确定它们结合到细胞伴侣热休克蛋白90（Hsp90）上的一个共同位点。在没有受体结构的情况下，NAMFIS已在CDCl3溶液中鉴定出格尔德霉素和雷迪西醇的生物活性构象，其丰度分别为4%和21%。相反，将NAMFIS构象集与GLIDE对接至未结合配体的蛋白质，然后进行MM-GBSA评分，可重现实验晶体学结合构象。
