Quantum-chemically-calculated mechanistically interpretable molecular descriptors for drug-action mechanism study – a case study of anthracycline anticancer antibiotics

Abstract

Identification of drug-action mechanisms and understanding of chemical substituents affecting the anticancer activity of drugs are important for drug development. However, the conventional QSAR methods show difficulty in serving these purposes because a certain amount of molecular descriptors are difficult to be interpreted; however, they have low-cost and time-saving features. As such, mechanistically interpretable molecular descriptors were developed in this study in order to make the technique of the structure–activity relationship useful in the drug-action mechanism study. The structure–activity plots of the anthracycline anticancer activity (log GI₅₀) against the mechanistically interpretable molecular descriptors: the polarizability (intercalation between the bases of DNA), the function in the dispersion interaction formula (passive diffusion through the lipid bilayers of cell membranes) and the energy change for the one-electron reduction (oxidative stress) were constructed. The descriptors were calculated by quantum chemical methods. The GI₅₀ values were obtained from the NCI-60 DTP human tumor cell line screen. This study shows that the intercalation strength and the passive diffusion rate dominantly contribute to cytotoxicity, but not the one-electron reduction according to the structure–activity plots. Therefore, the controversies of their contributions to cytotoxicity arising from the early experimental results are resolved. Moreover, the plots can describe how different chemical substituents affect anticancer activity. Also, the plots reveal that anthracyclines not only bearing morpholino and cyanomorpholino moieties and three-sugar-like units can behave with extraordinary anticancer activity, and the situations are more complicated than simply possessing them. Accordingly, the results challenge the current proposals for the design of anthracycline anticancer antibiotics, and reviewing the drug design strategies is necessary.