Droloxifene

Estrogen receptors, particularly ERα, play a key role in breast cancer progression, making them prime targets for therapeutic intervention.Tamoxifen (TAM), a selective estrogen receptor modulator (SERM), has been widely used for the treatment of ER+ breast cancer; however, its clin. application is limited by side effects and the emergence of resistance.This study aims to identify and evaluate TAM analogs with improved efficacy and reduced side effects by employing mol. docking and mol. dynamics (MD) simulations.Droloxifene, endoxifen, and afimoxifene emerged as promising candidates, exhibiting strong binding affinities with ERα, as indicated by highly neg. binding energy (BE) values in docking simulations.MD simulations further validated the stability of the complexes formed between these analogs and ERα, with low root mean square deviation (RMSD) values and stable radius of gyration (Rg) profiles.Root mean square fluctuation (RMSF) anal. revealed balanced flexibility, with droloxifene and afimoxifene showing optimized flexibility for stable binding.Hydrogen bond anal. indicated more stable interactions between these analogs and ERα compared to TAM, suggesting enhanced binding affinity.MM/GBSA binding free energy anal. confirmed the high affinity of these analogs, with droloxifene displaying the most effective binding free energy (ΔG_total) value.ADMET profiling suggests that droloxifene and endoxifen have superior pharmacokinetic properties relative to TAM.Overall, droloxifene, endoxifen, and afimoxifene represent promising alternatives to TAM, with the potential for further clin. development in breast cancer treatment.Exptl. validation in cell-based and in vivo models will be crucial in future studies to confirm their efficacy and safety profiles.