Pharmacophore search for anti-fertility and estrogenic potencies of estrogen analogs
Estrogen mediates its action following binding to the estrogen receptor to form an estrogen-receptor complex. The complex initiates gene transcription and produces estrogen-induced cell and/or tissue responses, i.e., estrogenic actions. High doses of estrogen can be used effectively as a contraceptive but are associated with side effects. Considering the long-term benefit-to-risk ratio of estrogen analogs as oral contraceptives, the present study was performed to deduce the active pharmacophore features required to differentiate the anti-fertility potency from the estrogenic activity of the steroidal motif. Implementing classical quantitative structure-activity relationship (QSAR) studies, substitution by an electron-donating group at the C-17 position and the presence of a hydrogen bond acceptor at C-11, along with the orientation and conformational rigidity of the molecule, were found to be critically important features for estrogenic potency, including anti-fertility activity. However, low electron density at C-2 and high electronegativity at C-16, which may be due to substitution on those and/or neighboring atoms, favor contraceptive potency, whereas high electron density at C-5 and substitution by an electron-withdrawing group at C-7, which may confer hydrophobicity on the steroidal scaffold and an overall increment of electron affinity of the molecule, are favorable for estrogenicity. Further CATALYST-based 3D space modeling demonstrates that the presence of the aromatic ring (ring A), hydrophobic zone (ring B), and hydrogen bond acceptor at C-17 in ring D, along with steric influence due to conformational rigidity of the compound, impart estrogenic contraceptive activity, but the presence of a second acceptor in ring A, and the critical distances between these features, selectively differentiate the anti-fertility potency from the estrogenic activity.
anti-fertility and estrogenic potency estrogen quantitative structure-activity relationship pharmacophore space modeling