Theoretical Investigation of Mitomycin Derivatives as Dual Inhibitors of HER2 and ER-α: Prospects for Novel Breast Cancer Treatment Strategies
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Abstract
Background: Breast cancer remains one of the most prevalent and challenging malignancies worldwide, largely due to its high heterogeneity and the development of resistance to conventional therapeutic agents. Mitomycin, a potent antitumor antibiotic, has demonstrated clinical efficacy; however, its therapeutic application is often restricted by systemic toxicity and emerging drug resistance.
Objective: This study aims to design and evaluate novel Mitomycin derivatives with optimized pharmacokinetic properties and enhanced binding affinities toward critical molecular targets associated with breast cancer, utilizing a range of advanced in silico approaches.
Methods: A library of Mitomycin derivatives was computationally designed and assessed for their pharmacokinetic and toxicity profiles using SwissADME and ProTox-II platforms. Molecular docking studies were conducted with Schrödinger Maestro to predict the binding interactions of the compounds with breast cancer-relevant proteins. The top-performing analogues were subsequently subjected to 100-nanosecond molecular dynamics (MD) simulations via Desmond to evaluate the dynamic stability of the ligand-protein complexes under simulated physiological conditions.
Results: Several designed compounds exhibited promising ADMET profiles alongside strong binding affinities against the selected breast cancer targets. Notably, Mitomycin-3 and Mitomycin-8 achieved the most favorable docking scores and demonstrated high stability during MD simulations, maintaining root-mean-square deviation (RMSD) values below 2.5 Å and displaying minimal structural fluctuations throughout the simulation period.
Conclusion: The results underscore Mitomycin-3 and Mitomycin-8 as promising therapeutic candidates with improved pharmacokinetic characteristics and stable interactions with key breast cancer targets, supporting their potential development as more effective agents for breast cancer treatment.
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References
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