QSAR Studies with E-State Index: Predicting Pharmacophore Signals for Estrogen Receptor Binding Affinity of Triphenylacrylonitriles

Abstract

Estrogens are endocrine regulators of both the male and female reproductive systems like the mammary gland, uterus, ovary, testis and prostate. They also play essential roles in non-target tissues, e.g., bone, liver, or in the cardiovascular system, where estrogens have protective actions.1-3) Such effects on different organs are the result of the interaction with the estrogen receptor (ER), of which two subtypes (ER a and ER b ) are presently known. 4,5) The interaction with ER is also involved for the treatment in a range of diseases such as breast cancer, osteoporosis, endometrial cancer, and prostate hypertrophy.6) ER is a member of the nuclear hormone receptor super family.7) The principal endogenous ligand for ER in most species is 17b estradiol (E 2 ). Over the years, many synthetic ligands have been investigated as potential analogues of E 2 , 8,9) in the search for agents that would be useful in regulating fertility, in preventing and treating breast cancer and other therapeutic areas. Selective estrogen receptor modulators (SERMs) that show tissue-dependent agonistic or antagonistic behavior, are used as first line treatment for estrogenresponsive breast cancer and for therapy against osteoporosis. 10,11) This pure estrogen antagonists (anti-estrogens) are currently in clinical development for breast cancer treatment. 12)Several estrogenic triphenylethylenes having an NO 2 , Cl or ethyl fragment as fourth substituent on the ethylene have been investigated as therapeutic agents.13) We had earlier established some basic pharmacophore features of different triphenylethylenes with trifluoromethyl as the fourth substituent.14) Consequently, the present work was taken up as continuation of the previous attempt in defining pharmacophore signals of different triphenylethylenes and is based on a series of triphenylethylenes with CN as the fourth substituent. The estrogenic activities exhibited by hydroxy, methylated substituents and bulky functional groups on different triphenylacrylonitrile derivatives have been reported. 15,16) The present study explores selectivity requirements of such diverse sequence of hydroxylated and non-hydroxylated triphenylacrylonitriles, including compounds with bulky hydrophobic substituents for binding to calf uterus estrogen receptor (ER). 17)Structure-activity relationships has been drawn, investigating topological features of constituting atoms of the triphenylacrylonitrile molecular architecture for characterization of unique pharmacophore features.Topological models directly give structural information to guide design of new molecules 18) and may predict three-dimensional structural parameters, as well.19) The electrotopological state (E-State) of atoms has proved to be a significant tool in elucidating major drug-receptor interactions. [20][21][22] An atom in a molecule is part of a field of information with regard to electronic influences and topological surrounding. 20,23) Quantification of influence of this field on any atom, can correlate to the biological performance of...

Molecular Design Based on Receptor-Independent Pharmacophore: Application to Estrogen Receptor Ligands

“…26,43) All the compounds are imported into spreadsheet of hypothesis generation workbench and activity is estimated. A correlation coefficient of 0.977 shows a good relation between the actual and estimated activities (Fig.…”

“…Our group has explored the prime pharmacophore signals for estrogen mediated bioactivities of a different group of compounds through Quantitative Structure Activity Relationships (QSAR) studies. [24][25][26] Attempts range from the use of simple two-dimensional 27) graph theoretical parameters and semiemperical quantum chemical methods 28) to highly sophisticated three dimensional (3D) approaches. [29][30][31][32][33][34] Structurally diverse 60 environmental estrogens 27) are classified through QSAR studies.…”

Binding Affinity of Triphenyl Acrylonitriles to Estrogen Receptors: Quantitative Structure-Activity Relationships

“…The sample of triphenyl acrylonitriles previously studied by Mukherjee et al 13 was included in analysis. The compound abbreviation, 2D structure and estrogenic activity expressed as relative binding affinity to the ER vis-à-vis E2 in logarithmic scale (logRBA) are given in Fig.…”

Normal probability plots with confidence

“…We use the real data from the case study of the estrogen receptor binding affinity of triphenilacrylonitriles (ERBAT) reported in Mukherjee et al. () to illustrate the graphical tests. Twenty five observations on ERBAT in a simple random sample are given by −1.046, 1.556, 0.342, 0.519, 1.792, 1.869, 0.785, 2.22, 1.447, 0.398, 1.968, 1.892, 0.959, −0.18, 1.23, −0.444, 0.806, −2, 0.531, 2.033, −0.398, −2, −1.398, 2, and −1.398.…”