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

Area of Science:

• Pharmacology
• Computational Chemistry
• Drug Discovery

Background:

• Increasing cancer incidence necessitates effective antineoplastic drugs.
• Current drugs like Capecitabine cause severe toxicities due to non-specific binding and off-target effects.
• Limited understanding of drug mechanisms hinders the development of safer alternatives.

Purpose of the Study:

• To investigate the side effects of Capecitabine, an antineoplastic drug.
• To identify natural analogs of Capecitabine with comparable efficacy but reduced toxicity.
• To explore novel strategies for discovering safer cancer therapeutics.

Main Methods:

• Literature review on Capecitabine-induced toxicity.
• Screening of 723,878 natural compounds for drug-like mimics.
• Molecular docking to assess binding affinity with Thymidine Phosphorylase (TP) and Dihydropyrimidine dehydrogenase (DPD).
• Molecular Dynamics (MD) simulations for validation of binding and conformational stability.

Main Results:

• Four natural compounds demonstrated superior docking scores compared to Capecitabine.
• MD simulations confirmed the stability of the most promising natural analog.
• The study identified potential drug-like mimics with improved binding profiles.

Conclusions:

• Natural analogs offer a promising avenue for developing safer antineoplastic drugs.
• This study presents a novel lead identification approach for discovering therapeutics with reduced adverse effects.
• The findings pave the way for next-generation cancer treatments with enhanced safety profiles.