In Silico Drug Design and Virtual Screening of Novel Tamoxifen and Mitomycin Derivatives : ADMET Profiling, Molecular Docking, and Molecular Dynamics Simulations
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Date
2025
Journal Title
Journal ISSN
Volume Title
Publisher
جامعة الوادي university of eloued
Abstract
Breast cancer is one of the most significant global public health challenges, particularly
in its subtypes characterized by hormone receptor positivity or HER2 protein overexpression,
which require effective and targeted therapeutic strategies. Tamoxifen, a selective estrogen
receptor modulator, is widely used; however, the development of cancer cell resistance often
limits its efficacy. In contrast, Mitomycin, a DNA-interfering antitumor antibiotic, has shown
promising activity, making it a molecule of interest for novel drug development.
This study aims to design and evaluate 256 analogues for both Tamoxifen and Mitomycin
using advanced computational approaches, including pharmacokinetic and toxicological
profiling (ADMET), molecular docking, and molecular dynamics (MD) simulations. Results
revealed that Tamoxifen analogues Tmx1, Tmx3, and Tmx4 demonstrated LD₅₀ values ranging
from 1500 to 1530 mg/kg (toxicity class 4), were non-hepatotoxic (hepatotoxicity values
between -0.50 and -0.53), and non-immunotoxic (up to -0.99), with low mutagenic and
carcinogenic potential. During MD simulations, these compounds showed RMSD values below
2.5 Å, indicating high structural stability.
On the other hand, the Mitomycin6 compound stood out with an LD₅₀ of 3000 mg/kg
(toxicity class 5), very low hepatotoxicity (-0.51), negligible immunotoxicity (-0.99), strong
biological activity, and excellent structural stability during simulations.
Based on these findings, Tmx1, Tmx3, Tmx4, and Mitomycin6 are considered promising
next-generation targeted therapy candidates for breast cancer, offering a balanced profile of
efficacy and drug safety.
Description
Keywords
Breast cancer, Tamoxifen analogues, Mitomycin6, HER2, ER-α, molecular docking, molecular dynamics, drug design, ADMET, targeted therapy.
Citation
master, 2025. DEPARTEMENT DE BIOLOGIE CELLULAIRE ET MOLECULAIRE. Faculté des Sciences de la Nature et de la Vie. Université d'El-Oued.