In Silico Screening of Theophylline Derivatives for Anticancer Activity: Integrating Molecular Docking, ADMET Predictions, and Molecular Dynamics Simulations

Introduction: Aldehyde dehydrogenase ۱A۱ (ALDH۱A۱) is an enzyme involved in cellular detoxification and plays an important role in maintaining cancer stem cells and chemoresistance. This study explores the potential of four theophylline derivatives (compounds A, B, C, and D) as ALDH۱A۱ inhibitors using molecular docking, ADME analysis, toxicity predictions, and molecular dynamics simulations. Materials and Methods: Four compounds were chosen based on their strong experimental and predicted biological activities. Docking with human ALDH۱A۱ was performed using AutoDock Vina (v۱.۱.۲), while ADMET properties were assessed with ADMETlab ۳.۰ and ProTox ۳.۰. Molecular dynamics simulations were carried out with GROMACS ۲۰۲۴.۲ to evaluate the dynamic behavior and binding stability of the complexes. Results: Molecule A showed the highest binding affinity (–۱۱.۳ kcal/mol) and established substantial interactions with important residues such as TRP۱۷۸, TYR۲۹۷, and PHE۱۷۱. ADMET analysis indicated that compounds A and C have high intestinal permeability, and all compounds displayed low toxicity risks, supporting their promise as therapeutic candidates. Molecular dynamics simulations confirmed that ALDH۱A۱’s overall structure remains stable during the simulation and revealed strong hydrogen bonding in complex A, as supported by favorable RMSD, SASA, and RMSF values. Conclusions: The integrated approach combining molecular docking, ADMET analysis, and molecular dynamics simulations confirms that Molecule A is the most promising ALDH۱A۱ inhibitor, exhibiting stable binding, favourable pharmacokinetic properties, and robust interactions with several residues. These results provide a strong foundation for further experimental validation and optimization in the development of targeted cancer therapies.

کلیدواژه ها:

Theophylline derivatives ، ALDH۱A۱ Inhibitors ، cancer ، Molecular docking ، ADMET ، Molecular Dynamics