In silico investigations of inhibition capabilities of selective estrogen receptor modulators against estrogen receptor - α (ER-α) in breast cancer.

Selective Estrogen Receptor Modulators (SERMs) represent a critical therapeutic approach in hormone-dependent breast cancer, specifically in cases fueled by the ER-α. This comprehensive study presents a comparative evaluation of three prominent selective estrogen receptor modulators (SERMs), including two benzothiophene-derived compounds, Raloxifene and Arzoxifene, and one tetrahydronaphthalene-based molecule, Lasofoxifene, using an integrated computational approach. Utilizing advanced computational techniques, the molecular docking investigations identified Lasofoxifene possess the highest binding affinity towards ER-α among the studied SERMs, which were subsequently investigated through extensive molecular dynamics (MD) simulations to elucidate the stability and interaction behavior of the ER-α - SERM complexes over nanosecond timescales. In particular, the ER-α complexes with Lasofoxifene and Arzoxifene exhibit more compactness and structural stability of the receptor, based on their radius of gyration and hydrogen bond analysis data. However, principal component analysis (PCA) reveals the nature of conformational fluctuations in the ER-α - Lasofoxifene complex, indicating a reduced conformational state compared to the other complexes. Further, the binding free energy analysis using the MM-PBSA approach displayed the most favorable energetic profile corresponding to the ER-α - Lasofoxifene complex, governed predominantly by the hydrophobic interactions within the binding pocket. A combined evaluation of docking scores, stability parameters, and energetic profiles consistently identifies Lasofoxifene as forming the most stable complex with ER-α among the investigated ligands. So, the investigations provide a molecular-level understanding of ER-α inhibition and highlight Lasofoxifene as a promising candidate with strong inhibitory potential.