Phytoestrogens Modulate Bovine G Protein‐Coupled Receptors and Play a Critical Role in Regulating Reproductive Functions in Animals

Phytoestrogens are secondary plant metabolites that are structurally analogous to endogenous oestrogens and bind to Bovine G Protein-Coupled Receptors (GPCRs) in animals. Their interaction with GPCRs activates intracellular signalling cascades, such as the cAMP/PKA pathway, which plays a crucial role in ovarian follicle development and luteinisation. These interactions may enhance reproductive performance by improving fertility, synchronising estrous cycles, and promoting ovulation. Phytoestrogens also influence the regularity and timing of the estrous cycle, offering potential applications in estrous synchronisation and reproductive management. In this study, molecular docking was conducted on 12,000 phytochemicals to identify potential GPCR ligands. From this extensive screening, five compounds with the highest binding affinities to GPCRs were selected. Notably, Genistein and Apigenin emerged as top candidates, with docking scores (-8.58 kcal/mol and -8.27 kcal/mol) and lower RMSD values (0.69 and 1.30) compared to synthetic GPCR agonists such as Estradiol (-6.07 kcal/mol and 1.02), respectively. Molecular dynamics simulations (MDS) confirmed the stability of these phytoestrogen -GPCR complexes, suggesting effective and sustained interactions. The screened phytoestrogens demonstrated favourable pharmacokinetic profiles, including non-toxicity, non-carcinogenicity, and high gastrointestinal absorption, positioning them as viable candidates for enhancing reproductive performance in dairy cattle through GPCR modulation. These findings suggest that phytoestrogens could be used as feed additives to improve reproductive outcomes, offering a novel approach to modulate GPCR pathways in dairy animals.