Siu-Kwong Pang*Pages 600-607 (8)
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.
Anthracyclines, electrophilicity, dispersion interaction, drug toxicity, quantitative structure-activity relationship, quantum chemical methods.
Institute of Textiles and Clothing, Faculty of Applied Science and Textiles, The Hong Kong Polytechnic University, Hung Hom, Kowloon