Three-dimensional model of nonsteroidal estrogen receptor ligand binding/electron topological method.

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been obtained using the electron topological method (ETM) for estrogen (estrone, CAS 53-16-7) receptor (ER) affinities. This method was used to identify regions of the enzyme and inhibitors where steric and electrostatic effects correlate strongly with biological activity. Thirty compounds belong to a series of diethylstilbestrol (CAS 56-53-1, DES) and indenestrol (CAS 24643-94-5) analogues whose affinities for ER have been, theoretically, investigated. After energy minimizations and molecular dynamics calculations were performed to find the ground state conformer for each molecule, quantum chemical properties of each molecule were defined and in ETM their matrices were compared with those of the reference molecule. It is shown that the molecular fragments responsible for this affinity possess fixed electronic and geometric characteristics associated with a distinct arrangement and steric accessibility of an oxygen atom and a group of carbon atoms. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities. The highest correlation coefficient (R2 = 0.930, SE = 0.403) was obtained with the structure of the active fragment and the orientation of aliphatic and phenolic substituents.