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

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Abstract

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 ERα and ERβ exhibited a parabolic relationship with dipole moment (μ). The high-affinity binding of PEs to ERα correlated with Dif0(0χ-0χv difference index encoding nonsigma electronic charge), while the low-affinity binding of PEs to ERα correlated with H bonding (positive coefficient) and % hydrophilic surface (negative coefficient). The high-affinity binding of PEs to ERβ correlated with molecular with (MWd) and Dif0, while the low-affinity binding of PEs to ERβ 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 ERα correlated with Dif0-Dif1, while RTA of ERβ correlated with H bonding and polarity. The PE-induced stimulation of DNA synthesis in estrogen-sensitive breast cancer (BC) cells correlated positively with {MD*4χv} where MD is molecular depth and 4χv 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-3χv 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.

Original languageEnglish (US)
Pages (from-to)201-216
Number of pages16
JournalCancer Investigation
Volume19
Issue number2
DOIs
StatePublished - Apr 3 2001

Keywords

  • Cancer protection, Cancer stimulation
  • DNA synthesis
  • Phytoestrogens
  • QSAR

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