Development of QSAR models to predict estrogenic, carcinogeic, and cancer protective effects of phytoestrogens

An integrated QSAR model has been formulated to predict estrogenic, carcinogenic, and cancer protective effects of phytoestrogens (PE). Relative binding of PEs to estrogen receptors ER_α and ER_β exhibited a parabolic relationship with dipole moment (μ). The high-affinity binding of PEs to ER_α correlated with Dif₀(⁰χ-⁰χ^v difference index encoding nonsigma electronic charge), while the low-affinity binding of PEs to ER_α correlated with H bonding (positive coefficient) and % hydrophilic surface (negative coefficient). The high-affinity binding of PEs to ER_β correlated with molecular with (MWd) and Dif₀, while the low-affinity binding of PEs to ER_β correlated with H bonding (positive coefficient) and hydrophilic-lipophilic balance (negative coefficient). Thus an increase in electronic or ionic charge, formation of H bonds, or a decrease in hydrophilic property of PEs may increase their binding to ER. The relative transcription activity (RTA) of ER_α correlated with Dif₀-Dif₁, while RTA of ER_β correlated with H bonding and polarity. The PE-induced stimulation of DNA synthesis in estrogen-sensitive breast cancer (BC) cells correlated positively with {MD*⁴χ^v} where MD is molecular depth and ⁴χ^v is the valence of a 4th order fragment. IC₅₀ for PE-induced inhibition of DNA synthesis in estrogen-sensitive BC cells correlated with {MD* Log P} and Dif₃ (³χ-³χ^v difference index encoding nonsigma electronic charge of fragments consisting of four atoms and three bonds) and Diff²₃. IC⁵⁰ for PE-induced inhibition of DNA synthesis in estrogen-independent cancer cell lines correlated with {MD* Log P) and 1/water solubility. Thus molecular shape and molecular connectivity of PEs play a key role in modulating estrogen-induced transactivation activity and DNA synthesis in BC cells.