蒽环类抗癌抗生素的氧化还原、生物转化和传递：利用嗜电性和伦敦扩散公式解释致命性的结构-活性关系论互动工作

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.

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