title: Development of QSAR models to predict estrogenic, carcinogenic, and cancer protective effects of phytoestrogens.
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 ER alpha and ER beta exhibited a parabolic relationship with dipole moment (mu). The high-affinity binding of PEs to ER alpha correlated with Dif0 (0 chi-0 chi v difference index encoding nonsigma electronic charge), while the low-affinity binding of PEs to ER alpha correlated with H bonding (positive coefficient) and % hydrophilic surface (negative coefficient). The high-affinity binding of PEs to ER beta correlated with molecular with (MWd) and Dif0, while the low-affinity binding of PEs to ER beta 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 alpha correlated with Dif0-Dif1, while RTA of ER beta correlated with H bonding and polarity. The PE-induced stimulation of DNA synthesis in estrogen-sensitive breast cancer (BC) cells correlated positively with (MD*4 chi v) where MD is molecular depth and 4 chi 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 (3 chi-3 chi v difference index encoding nonsigma electronic charge of fragments consisting of four atoms and three bonds) and Dif3(2). 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.
authors: Department of Veterinary Diagnostic Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, St. Paul, Minnesota, USA.
authors: A K
authors: AK
authors: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002273:Carcinogens / Q000493:pharmacokinetics; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens / Q000493:pharmacokinetics; D004968:Estrogens, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007529:Isoflavones; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D048789:Phytoestrogens; D028321:Plant Preparations; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D004968:Estrogens, Non-Steroidal; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen