SYNTHESIS OF CARDIOVASCULAR POLYETHER ANTIBIOTICS

心血管聚醚抗生素的合成

• 批准号: 2392589
• 负责人: WILLIAM C STILL
• 金额: $ 31.91万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2392589
• 关键词: antibiotics; cardiovascular agents; chemical binding; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; ion transport; ionophores; monensin; neurotransmitter receptor; antibiotics; cardiovascular agents; chemical binding; chemical models; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; ion transport; ionophores; monensin; neurotransmitter receptor

Naturally occurring polyether ionophores (e.g. lasalocid, monensin) have important inotropic properties. It is believed that these properties are a function to the ability of such molecules to bind and transport cations across biological membranes. The objective of this proposal is to develop powerful methods by which new, artificial ionophores which have highly selective cation-binding and transporting properties may be designed and prepared. Previous work has shown that the highest selectivity for binding closely related cations is found with ionophores which have limited conformational flexibility. In this application, I propose designs and syntheses of a series of new, podand ionophores which are conformationally homogeneous nd thus are more rigid than most previously studied ionophores. We will determine the three-dimensional structures and binding properties of these new ionophores in order to establish the relationship between their chemical structures and ionophoric properties. We will use the data obtained to validate a computational method using free energy perturbation for predicting the ionophoric properties of new ionophores. A key goal of this proposal is to develop a reliable computational tool which allows hypothetical designs for new ionophores to be tested by a calculation for their ion- binding or transporting properties. Such a tool would allow the design of optimally selective new ionophores prior to time-consuming synthesis.

天然存在的聚醚离子载体（例如Lasalocid，Monensin）具有 重要的肌力性质。 相信这些属性 是这种分子结合和转运能力的功能 跨生物膜的阳离子。 该提议的目的是 开发新的人造离子载体的强大方法 具有高度选择性的阳离子结合和运输特性 设计和准备。 以前的工作表明最高 与离子载体发现结合紧密相关的阳离子的选择性 构象柔韧性有限。 在此应用程序中，我 提出了一系列新的，波音的离子载体的设计和合成 因此，它们在构象上均质ND比大多数 先前研究的离子载体。 我们将确定三维 这些新离子载体的结构和结合特性是为了 建立化学结构与 离子性特性。 我们将使用获得的数据来验证 使用自由能扰动来预测的计算方法 新离子载体的离子性特性。 该提议的关键目标是 开发可靠的计算工具，该工具允许假设 通过计算其离子 - 结合或运输特性。 这样的工具将允许设计 在耗时的合成之前，最佳选择性的新离子载体。