Design, Synthesis, Molecular Docking, Dynamics Simulation, and Biological Evaluation of Novel Thiazolidinedione...

Breast cancer remains one of the leading causes of cancer-related deaths among women worldwide. The chemotherapeutic drugs used in treatment often have serious side effects. In light of their anticancer potential, thiazolidinedione (TZD) derivatives are considered to be promising candidates for the development of novel antitumor agents. The objective of this study is to synthesize and produce two sets of TZD derivatives by combining the structural features of microtubule-targeting drugs used in breast cancer treatment, and to determine their molecular docking, molecular dynamics simulations, ADMET profile, antiproliferative, and apoptotic effect potential. In the present study, PZ-11 was determined by xCELLigence analysis to have the highest antiproliferative potential among all compounds tested on MCF-7 breast cancer cells. The cytotoxic activity of the synthesized compounds was evaluated against MCF-7 breast cancer cells, revealing IC₅₀ values of 29.44 μM for PZ-9 and 17.35 μM for PZ-11, compared to 6.45 μM for the reference drug vincristine. Analysis of the gene expression of the PZ-11 compound, which has a stronger cytotoxic effect potential, showed that PZ-11 significantly downregulates AIFM1, BAG3, and BIRC3, while upregulating pro-apoptotic genes such as BAD, HRK, CASP10, and CASP14. PZ-11's binding affinities were screened using a molecular docking workflow via KNIME. The robust and persistent interactions between PZ-11 and AIF were substantiated by molecular dynamics simulation. It is demonstrated by ADMET predictions that PZ compounds possess suitable pharmacokinetic properties. PZ-11 is a promising TZD-based anticancer drug candidate against breast cancer cells, as determined by computational and experimental analysis. However, further validation is required through in vivo analysis to support these findings.