DNA BINDING OF ANTITUMOR DRUGS--COMPUTER ANALYSIS

抗肿瘤药物的 DNA 结合--计算机分析

• 批准号: 3175637
• 负责人: WILLIAM A REMERS
• 金额: $ 6.35万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1987-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3175637
• 关键词: DNA; alkylation; anthracenes; chemical binding; chemical structure function; computer data analysis; computer graphics /printing; dinucleotide; drug design /synthesis /production; mathematical model; mitomycins; molecular biology; nuclear magnetic resonance spectroscopy; physical chemical interaction; statistics /biometry

The long-term objective of the proposed research is to obtain valid representations for the binding of mitomycins and certain anthracenes to DNA, in order to design new, improved agents more rationally. We have experience in the chemistry and spectroscopy of these agents and many analogues with interesting structural features and proven antitumor activity are on hand. The DNA binding of these compounds will be studied on a theoretical level by molecular mechanics and computer graphics. Experimental studies on binding will be made in order to test the theoretical models and to help simplify the computer searches of random drug-DNA interactions. Although the mode of mitomycin binding to DNA has been studied by numerous investigators, much of it is uncertain. It is known that mitomycins are activated by bioreduction and that the resulting reactive intermediates bind with and alkylate DNA. Recently, some of the sites of alkylation have been defined by analysis of DNA hydrolysates. However, the reactivity of the putative intermediates precludes their isolation. We wish to consider the initial non-covalent binding of two structures proposed as intermediates, examining how their calculated electrostatic potential surfaces might have complementarity with certain regions of DNA, and if such complementarity correlates with the known binding sites. Also to be investigated is the approach of these intermediates to DNA using a "docking" algorithm, with the known sites of covalent binding invoked to simplify the selection of "best" answers from many possible ones. Anthracene derivatives to be investigated include structures related to bisantrene, mitoxantrone, and a promising new type that we have discovered. These compounds are all on hand and they have been tested for comparative potencies in human tumor clonogenic assays. Anthracenes are thought to be intercalating agents. Theoretical representations will be derived for the intercalation of anthracenes and they will be compared with 1H-nmr evidence obtained on anthracene-dinucleotide complexes. Binding energies will be calculated and compared with those determined experimentally. Quantitative structure-activity relationships will be derived using these binding energies and potencies in antitumor assays.

拟议研究的长期目标是获得有效 丝裂霉素和某些蒽与结合的表示 DNA，为了更合理地设计新的，改进的代理。 我们有 这些药物的化学和光谱经验以及许多 具有有趣的结构特征和经过验证的抗肿瘤的类似物 活动在场。 将研究这些化合物的DNA结合 在理论上，分子力学和计算机图形。 将进行有关结合的实验研究，以测试 理论模型并帮助简化计算机搜索的随机搜索 药物-DNA相互作用。 尽管丝裂霉素与DNA结合的模式已经通过许多 调查人员，其中大部分尚不确定。 众所周知，丝裂霉素是 通过生物补充激活，并产生的反应性中间体 与烷基化DNA结合。 最近，一些烷基化的位置具有 通过分析DNA水解物来定义。 但是，反应性 推定的中间体排除了它们的隔离。 我们想考虑 提出的两个结构的初始非共价结合 中级，检查其计算静电电势如何 表面可能与某些DNA区域具有互补性，如果 这种互补性与已知的结合位点相关。 也是 研究是这些中间体使用A的方法 “对接”算法，并带有共价结合的已知位点 简化许多可能的答案的“最佳”答案。 要研究的蒽衍生物包括与 双弯曲，mitoxantrone和我们拥有的一种有希望的新型 发现。 这些化合物都在手头，已经进行了测试 人肿瘤克隆性测定中的比较效力。 炭疽病是 被认为是插入剂。 理论表示将是 源自炭疽烯的插入的派生，将与它们进行比较 1H-NMR证据在蒽二核苷酸复合物上获得。 结合 将计算能量并将其与确定的能量进行比较 实验。 定量结构活动关系将是 在抗肿瘤测定中使用这些结合能和效力得出。