In Silico Drug Design and Virtual Screening of Novel Tamoxifen and Mitomycin Derivatives : ADMET Profiling, Molecular Docking, and Molecular Dynamics Simulations

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.