摘要
背景:量子化学方法和分子力学方法在药物代谢研究中面临着许多挑战,因为它们要么是精确度不够,要么是计算量大,要么是缺乏c。用于建立计算模型的李尔分子水平图。低成本的qsr方法通常可以实现,尽管分子水平的图像没有很好的定义,但是它们显示出困难。确定药物代谢机制和描述化学结构对药物毒性的影响,因为一定数量的分子描述符难以解释。. 目的:利用机械解释的分子描述符与生物活性相关联,建立结构-活性图,以实现QSAR的突破。比奥洛化学活性是蒽环类抗肿瘤抗生素的致死性,被称为log LD 50。机械解释的分子描述符包括亲电性和数学功能。伦敦色散相互作用公式中的离子。 方法:用量子化学方法计算描述子。 结果:电亲性图被解释为蒽环类化合物的氧化还原活性,可以描述氧化降解解毒和还原生物活化对毒性的影响。艾尔。分散相互作用函数图代表了蒽环类化合物和生物分子之间的吸引力,可以描述从毒性靶细胞流出和流入目标细胞的情况。。这些地块还可以识别三种具有不同代谢途径的蒽环类化合物的结构支架,从而导致它们的毒性行为不同。 结论:本研究揭示的结构依赖性毒性行为可为药物设计和药物代谢研究提供理论依据。
关键词: 蒽环类,嗜电性,分散相互作用,药物毒性,定量结构-活性关系,量子化学方法。
图形摘要
Current Cancer Drug Targets
Title:Redox Biotransformation and Delivery of Anthracycline Anticancer Antibiotics: How Interpretable Structure-activity Relationships of Lethality Using Electrophilicity and the London Formula for Dispersion Interaction Work
Volume: 18 Issue: 6
关键词: 蒽环类,嗜电性,分散相互作用,药物毒性,定量结构-活性关系,量子化学方法。
摘要: Background: Quantum chemical methods and molecular mechanics approaches face a lot of challenges in drug metabolism study because of either insufficient accuracy, huge computational cost, or lack of clear molecular level pictures for building computational models. Low-cost QSAR methods can often be carried out, even though molecular level pictures are not well defined; however, they show difficulty in identifying the mechanisms of drug metabolism and delineating the effects of chemical structures on drug toxicity because a certain amount of molecular descriptors are difficult to be interpreted.
Objective: In order to make a breakthrough of QSAR, mechanistically interpretable molecular descriptors were used to correlate with biological activity to establish structure-activity plots. The biological activity is the lethality of anthracycline anticancer antibiotics denoted as log LD50. The mechanistically interpretable molecular descriptors include electrophilicity and the mathematical function in the London formula for dispersion interaction.
Method: The descriptors were calculated using quantum chemical methods.
Results: The plots for electrophilicity, which is interpreted as redox reactivity of anthracyclines, can describe oxidative degradation for detoxification and reductive bioactivation for toxicity induction. The plots for the dispersion interaction function, which represents the attraction between anthracyclines and biomolecules, can describe efflux from and influx into the target cells of toxicity. The plots can also identify three structural scaffolds of anthracyclines that have different metabolic pathways, resulting in their different toxicity behavior.
Conclusion: This structure-dependent toxicity behavior revealed in the plots can provide perspectives on drug design and drug metabolism study.
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Cite this article as:
Redox Biotransformation and Delivery of Anthracycline Anticancer Antibiotics: How Interpretable Structure-activity Relationships of Lethality Using Electrophilicity and the London Formula for Dispersion Interaction Work, Current Cancer Drug Targets 2018; 18 (6) . https://dx.doi.org/10.2174/1568009617666170330145709
DOI https://dx.doi.org/10.2174/1568009617666170330145709 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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