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

Fadel, Fatima Zohra; Tchouar, Noureddine; Smail, Khadidja; Cheikh, Wafaa; Ait Tayeb, Mohammed Arab; Benmetir, Sofiane; Ouadah, Karim; Soualmia, Fatima; Medjahed, Sihem

doi:10.30491/jabr.2025.498830.1827

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

Document Type : Original Article

Authors

Fatima Zohra Fadel ¹^{, 1}

Noureddine Tchouar ¹

Khadidja Smail ¹^{, 2}

Wafaa Cheikh ¹

Mohammed Arab Ait Tayeb ¹

Sofiane Benmetir ¹^{, 3}

Karim Ouadah ¹

Fatima Soualmia ¹

Sihem Medjahed ¹

¹ Laboratory of Environmental Process Engineering (LIPE), Faculty of Chemistry, University of Science and Technology of Oran Mohamed Boudiaf (USTO-MB), BP 1505, El Mnaouer, Bir El Djir 31000, Oran, Algeria

² Department of Biotechnology, Faculty of Natural and Life Sciences, University of Science and Technology of Oran Mohamed Boudiaf (USTO-MB), BP 1505, El Mnaouer, Bir El Djir 31000, Oran, Algeria

³ Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicent Andrés Estellés s/n, 46100 Valencia, Spain

10.30491/jabr.2025.498830.1827

Abstract

Introduction: Aldehyde dehydrogenase 1A1 (ALDH1A1) 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 ALDH1A1 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 ALDH1A1 was performed using AutoDock Vina (v1.1.2), while ADMET properties were assessed with ADMETlab 3.0 and ProTox 3.0. Molecular dynamics simulations were carried out with GROMACS 2024.2 to evaluate the dynamic behavior and binding stability of the complexes.
Results: Molecule A showed the highest binding affinity (–11.3 kcal/mol) and established substantial interactions with important residues such as TRP178, TYR297, and PHE171. 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 ALDH1A1’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 ALDH1A1 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.

Keywords

Theophylline Derivatives

ALDH1A1 Inhibitors

Cancer

Molecular Docking

ADMET

Molecular Dynamics