Abstract

In target tissue, estrogens initiate a series of events, ending in protein synthesis, by binding to a cytoplasmic receptor. Once the estrogen binds, the receptor complex is activated--a process including dimerization of the estrogen complex with another subunit. In order to study the possible receptor-ligand interactions, conformational analysis was performed on several nonsteroidal estrogen analogs, using the CAMSEQ8 molecular mechanics program.

The probability that a molecule will exist in a given conformational energy well depends both on the energy and the shape of the well. A method has been previously worked out to calculate probabilities using both of these variables, on molecules in which only two torsional angles are rotated (Farnell 1974). A simplification of this method has been used to determine probabilities on molecules where more then two torsional angles are rotated (Kilbourn 1981). This simplification involves taking only one dimension of N-dimensional energy well into account when calculating probabilities. This thesis describes a method of calculating probabilities, on molecules in which more then two bonds are rotated, without making this simplifying assumption. Comparison of this approach with the simplified method demonstrates the importance of taking all N dimensions of an N-dimensional energy well into account when calculating probabilities.

Comparison of the binding data and conformational analysis of diethylstilbestrol (DES) and dimethylstilbestrol (DMS) demonstrates the importance of the ethyl groups to the binding affinity of estrogens to the estrogen receptor. In the analogs with saturated central bonds, binding affinity is not only related to the presence or absence of hydrophobic groups but is also related to the probability that the ligand exists in a planar conformation.

Low energy conformations of DES and meso hexestrol are compared to the x-ray structure of estradiol 17B. The topology of these conformations are studied using contour maps and distance diagrams. These maps and diagrams were constructed using information obtained from a pegboard which measures the three dimensional shape of a molecule. The similarities in these three estrogens, revealed in these studies, suggest the possibility that proteins may completely surround the estrogen.

Based on this idea, two representative models have been proposed to explain possible protein-estrogen and protein-antiestrogen interactions. The sandwich model envisions the estrogen acting as a connecting link between two monomers forming the 5S dimer. In the conformation model an estrogen binds to a 4S estrogen receptor monomer resulting in a protein conformational change which enables the monomer to dimerize.

LLU Discipline

Biochemistry

Department

Biochemistry

School

Graduate School

First Advisor

W. Bart Rippon

Second Advisor

R. Bruce Wilcox

Third Advisor

Charles W. Slattery

Fourth Advisor

David A. Hessinger

Fifth Advisor

Marvin Peters

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

1982

Date (Title Page)

3-1983

Language

English

Library of Congress/MESH Subject Headings

Estrogens, Synthetic; Estrogens, Non-Steroidal

Type

Dissertation

Page Count

210

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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