SYN MODELS FOR ELUCIDATING PACLITAXEL BINDING

用于阐明紫杉醇结合的 SYN 模型

• 批准号: 2821768
• 负责人: John S Williamson
• 金额: $ 10.88万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2821768
• 关键词: analog; binding sites; chemical models; chemical structure function; conformation; drug design /synthesis /production; drug receptors; nuclear magnetic resonance spectroscopy; paclitaxel; receptor binding; tubulin

DESCRIPTION: (Verbatim from the Applicant's Abstract) Paclitaxel is a novel diterpenoid which is now well established as a clinically active anticancer agent. Due to the complexity of the molecule, attempts to create paclitaxel analogs to obtain mechanistic information have been limited. Thus, there is relatively little information on the biochemical basis of this natural agonist at the tubulin binding site. Using crystal structure and NMR data, we have (along with several other groups) successfully computer-modeled the paclitaxel molecule in an aqueous environment. Contrary to other structures that have been modeled, for the most part in organic solvent, we have found that in water the paclitaxel molecule, to some degree, collapses upon itself. In this collapsed form, several functionalities, which are not likely neighbors in the traditional non-aqueous models, become extremely close to each other in space. Since in the body's aqueous environment, the paclitaxel molecule is most likely found in some form of the collapsed structure, we have postulated that the collapsed paclitaxel structure is likely to be an excellent model for the pharmacologically active shape. Thus, we are proposing the synthesis of several paclitaxel congeners that are "tied down" to mimic various stages of molecular collapse. Base on our computer-modeling data, we would expect these derivatives to show a high degree of binding specificity to the tubulin binding site.

产品说明：紫杉醇是一种新的二萜类化合物，目前已被公认为具有临床活性的抗癌剂。由于分子的复杂性，试图创建紫杉醇类似物以获得机理信息受到限制。因此，关于这种天然激动剂在微管蛋白结合位点的生物化学基础的信息相对较少。利用晶体结构和核磁共振数据，我们（沿着其他几个小组）成功地计算机模拟了水环境中的紫杉醇分子。与已经建模的其他结构相反，对于大部分在有机溶剂中，我们发现紫杉醇分子在水中在某种程度上会自我塌陷。在这种折叠形式中，几个功能，这是不太可能在传统的非水模型的邻居，变得非常接近彼此在空间中。由于在身体的水性环境中，紫杉醇分子最有可能以某种形式的塌陷结构被发现，因此我们假设塌陷的紫杉醇结构可能是活性形状的极好模型。因此，我们建议合成几种紫杉醇同系物，这些同系物被“束缚”以模拟分子崩溃的各个阶段。基于我们的计算机模拟数据，我们预期这些衍生物对微管蛋白结合位点显示出高度的结合特异性。