Computational framework for minimizing off-target toxicity in capecitabine treatment using natural compounds

Antineoplastic drugs are becoming prevalent due to increasing cancer casualties around the globe. However, the adverse effects of these drugs are evident due to limited insight into the underlying mechanisms that result in non-specific binding and consequent off-target toxicity. The study investigates the side effects of an antineoplastic drug, Capecitabine, a prodrug converted into fluorouracil by Thymidine Phosphorylase (TP) and degrades the RNA of cancerous cells. However, its non-specific binding with Dihydropyrimidine dehydrogenase (DPD) leads to severe toxicities including leukoencephalopathy, neutropenia, neuropathy, and others. Hence, identifying natural analogs of Capecitabine with comparable attributes is crucial for minimizing its adverse effects. A thorough review of the literature revealed Capecitabine-induced toxicity. 723,878 natural compounds were screened, and drug-like mimics were identified. Their binding with TP and DPD was determined by employing molecular docking, which was validated by MD simulations evaluating conformational stability and variability. Four natural compounds showed better docking scores than the standard drug. The stability of the best hit was further validated with MD simulations. This study, hence, ushers in new perspectives on safer drug alternatives using potent natural analogs and could serve as a lead identification approach for the discovery of safer therapeutics.