THEORETICAL AND QSAR STUDIES OF ANTHRACYCLINES AND THEIR ANALOGS

蒽环类药物及其类似物的理论和 QSAR 研究

• 批准号: 3841874
• 负责人: YITBAREK H MARIAM
• 金额: --
• 依托单位: CLARK ATLANTA UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3841874
• 关键词: DNA; anthracyclines; antineoplastic antibiotics; cardiotoxin; chemical models; chemical reaction; chemical structure function; conformation; cytotoxicity; daunorubicin; doxorubicin; drug design /synthesis /production; drug interactions; electron spin resonance spectroscopy; electronic spectra; free radicals; mass spectrometry; metal complex; nuclear magnetic resonance spectroscopy; quantum chemistry; radiotracer; tautomer

Theoretical studies of the reactivity of the anthracycline family of drugs will be undertaken using the AM1 formalism. The thrust of these studies is to gain insight from quantum chemistry/pharmacology, molecular modeling and statistical inference to understand molecular-level features that govern chemical reactivity but are concealed by the molecular structure and raw experimental data (Ref. 40). Tautomers, radicals/biradicals, possible intermediates and metabolites, metal complexes, etc. will be examined. Optimized geometries will be obtained and the relative stabilities will be determined on the basis of charge distribution, molecular orbital structures, etc. Relative reactivities will be probed using calculated molecular orbital energies (of HOMO, LUMO, SOMO). The origins of the relative stabilities and reactivities will be examined by energy- partitioning analysis. The computed electronic properties will be used, along with available experimental data, for QSAR/CoMFA studies to develop structure/activity (S/A) relationships. The S/A relationships developed this way will in turn be used to predict the biological activity of theoretical models - not-yet-synthesized drugs. Other studies will include reaction profiles/surfaces of models for formation of metabolites, conformational searches/minimum energy path calculations, transition state location, electron transfer reactions (metal to ligand and vice versa) by Mulliken population analysis, etc.

蒽环类药物的反应性的理论研究 将使用AM1形式主义进行。 这些研究的推力是 从量子化学/药理学，分子建模和 统计推断以了解控制分子级特征 化学反应性，但通过分子结构和原始 实验数据（参考文献40）。 互变异者，自由基/Biradicals，可能 将检查中间体和代谢物，金属配合物等。 将获得优化的几何形状，相对稳定性将是 根据电荷分布确定分子轨道 结构等。将使用计算的相对反应率进行探测 分子轨道能（HOMO，LUMO，SOMO）。 起源于 相对稳定性和反应性将通过能量检查 分区分析。 将使用计算的电子属性， 与可用的实验数据一起，用于QSAR/COMFA研究 结构/活动（S/A）关系。 S/A的关系发展 这种方式又将被用来预测 理论模型 - 尚未合成的药物。 其他研究将包括 用于形成代谢物的模型的反应曲线/表面， 构象搜索/最小能量路径计算，过渡状态 位置，电子转移反应（金属到配体，反之亦然） Mulliken人口分析，等等。