Phytoestrogens: Next generation ERα modulators in osteoporosis treatment – in silico approach and ADMET evaluation

Objective: Osteoporosis is a common metabolic bone disease caused by an imbalance between bone formation and resorption. Estrogen deficiency plays a critical role, especially in postmenopausal osteoporosis. The side effects of current treatments (bisphosphonates, SERMs) necessitate the investigation of safe phytoestrogen-based alternatives that exert a bone-protective effect via the estrogen receptor alpha (ERα). The aim of this study is to investigate the potential agonistic effects of nine different phytoestrogens on ERα using in silico methods. Materials and methods: In this study, molecular docking simulations were performed with phytoestrogens and the reference modulator tamoxifen using the ERα crystal structure (PDB: 3ERT). Binding affinities (kcal/mol) and ligand-protein interactions were determined with these simulations. In addition, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analyses were performed to evaluate drug similarity and safety profiles. Results: In docking analyses, coumestrol and genistein (-8.9 kcal/mol) stood out as the compounds with the highest binding affinity and achieved better scores than tamoxifen (-8.7 kcal/mol). These high-affinity compounds exhibited an agonistic binding mode similar to the native agonist and tamoxifen by forming hydrogen bonds with Glu353 and Arg394, key residues in the ERα ligand binding site. ADMET analyses showed that all phytoestrogens studied conformed to Lipinski rules and had generally acceptable pharmacokinetic and toxicity profiles. Conclusion: The obtained in silico data support the idea that phytoestrogens, particularly coumestrol, genistein, and daidzein, have the potential for tamoxifen-like agonistic activity by targeting ERα and could be developed as new and safer therapeutic agents in the treatment of osteoporosis.