Table Of ContentMolecular Structure
and
Biological Activity
of
Steroids
Edited by
Martin Bohl
Manager
TRIPOS Molecular Science Group
Evans & Sutherland Computer GmbH
Munich, Germany
William L. Duax
Research Director
Medical Foundation of Buffalo, Inc.
Buffalo, New York
Boca Raton London New York
CRC Press
CRC Press is an imprint of the
Boca TRaayltoor n& FraAncins nG roAupr, bano r infoLrmoan bduosinne ss Tokyo
First published 1992 by CRC Press
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
Reissued 2018 by CRC Press
© 1992 by CRC Press, Inc.
CRC Press is an imprint of Taylor & Francis Group, an Informa business
No claim to original U.S. Government works
This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been
made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity
of all materials or the consequences of their use. The authors and publishers have attempted to trace the copyright
holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this
form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we
may rectify in any future reprint.
Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or
utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including pho-
tocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission
from the publishers.
For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://
www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923,
978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For or-
ganizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.
Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for iden-
tification and explanation without intent to infringe.
Library of Congress Cataloging-in-Publication Data
Molecular structure and biological activity of steroids / editors,
Martin Bohl, William L. Duax.
p. cm.
Includes bibliographical references and index.
ISBN 0-8493-6955-X
1. Steroids--Structure-activity relationships. I. Bohl, Martin.
II. Duax, William L., 1939–
[DNLM: 1. Molecular Structure 2. Steroids--physiology.
3. Structure-Activity Relationship. QU 85 M718]
QP752.S7M65 1992
612.4’05--dc20
DNLM/DLC
for Library of Congress 92-4024
A Library of Congress record exists under LC control number: 92004024
Publisher’s Note
The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the
original copies may be apparent.
Disclaimer
The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been
unable to contact.
ISBN 13: 978-1-315-89570-3 (hbk)
ISBN 13: 978-1-351-07480-3 (ebk)
Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the
CRC Press Web site at http://www.crcpress.com
EDITORS
Martin Bohl, Ph.D., is manager of the TRIPOS Molecular Science Group
at Evans & Sutherland Computer GmbH, Munich, Germany.
Dr. Bohl obtained his training at the Friedrich Schiller University of Jena,
receiving the Diplom-Chemiker degree in 1974 and the Ph.D. degree in 1979.
After three years research work at the Jenaer Glaswerk, he joined the Academy
of Sciences of the G.D.R., Central Institute of Microbiology and Experimental
Therapy, Jena. During an eight-year period, his major interests included
computations of steroid structure and structure-activity relationships of ste-
roids. Since 1989 he has been working in the field of molecular modeling
within the TRIPOS group.
William L. Duax, Ph.D., is the Research Director of the Medical Foun-
dation of Buffalo, Buffalo, New York, Associate Research Professor, De-
partment of Biochemistry, Roswell Park Division of the State University of
New York at Buffalo, and Adjunct Associate Professor, Medicinal Chemistry
Department, School of Pharmacy, State University of New York at Buffalo.
Dr. Duax graduated from St. Ambrose College, Davenport, Iowa, with
a B.A. degree in 1961 and obtained his Ph.D. in Physical Chemistry in 1967
from the University of Iowa, Iowa City. He spent one year as a postdoctoral
fellow at Ohio University and came to the Medical Foundation as a Research
Associate in 1968. Dr. Duax was appointed Chairman of the Crystallography
Department in 1969, Head of the Molecular Biophysics Department in 1970,
Associate Research Director in 1983, and Research Director in 1988.
Dr. Duax is a member of the American Crystallographic Association,
The Biophysical Society, American Chemical Society, American Association
for Cancer Research, American Association for the Advancement of Science,
The Protein Society, The New York Academy of Sciences, and the Molecular
Graphics Society.
He served as President of the American Crystallographic Association in
1986 and is currently its Executive Officer. He was a member of the U.S.
National Committee for Crystallography from 1980 to 1991. He is on the
Board of Members of the American Institute of Physics, is Director of dis-
tribution of the Cambridge Structural Database to academic users in the United
States, was a Charter Member of the Commission on Small Molecules of the
International Union of Crystallography, and is its current Chairperson. Dr.
Duax was commissioned to the Honorable Order of Kentucky Colonels in
1982 and received a Distinguished Alumni A ward from St. Ambrose College
in 1983. He has been the recipient of many research grants from the National
Institutes of Health and currently holds a MERIT (Methods of Extending
Research in Time) award from the N.I.H., Institute of Arthritis and Metabolic
Disease.
Dr. Duax is co-author of 220 manuscripts and 39 chapters dealing with
the structure and function of steroid hormones, ion transport antibiotics, and
CNS active agents. He is co-editor of a two-volume Atlas ofS teroid Structure
and a text on Molecular Structure and Biological Activity. He has presented
130 invited lectures at national and international conferences and leading
research laboratories throughout the world, and is co-author of 230 abstracts
of scientific presentations at national and international meetings. Dr. Duax
has been on the organizing committees of dozens of symposia concerned with
the three-dimensional structure and biological activity of steroids, drugs, and
antibiotics.
CONTRIBUTORS
Martin Bohl, Ph.D. Seiichi lshizuka, Ph.D.
Manager Senior Researcher
TRIPOS Molecular Science Group Teijin Institute for Bio-Medical
Evans & Sutherland Computer Research
GmbH Hino, Japan
Munich, Germany
Kenneth S. Korach, Ph.D.
Philip A. Cole, M.D., Ph.D.
Senior Research Endocrinologist
House Officer
and Chief, Receptor Biology
Brigham and Women's Hospital
Section
and Harvard Medical School
Laboratory of Reproductive and
Boston, Massachusetts
Development Toxicology
National Institute of
Jean-Christophe Don~, Ph.D. Environmental Health Sciences
Research Scientist
Research Triangle Park, North
Laboratory of Computer
Carolina
Modelling
Centre National de Recherche
Sandor Mah6
Scientifique
Research Fellow
and Museum National d'Histoire
Research Laboratory of Organic
Naturelle
Chemistry
Paris, France
Chemical Works of
G. Richter Ltd.
William L. Duax, Ph.D.
Budapest, Hungary
Research Director
Medical Foundation of Buffalo
Buffalo, New York Kenji Mori, Ph.D.
Professor
Oldrich Hanc, Ph.D. Department of Agricultural
(Deceased) Chemistry
Research Institute of Pharmacy The University of Tokyo
and Biochemistry Tokyo, Japan
Prague, Czechoslovakia
Jean-Paul Mornon, Ph.D.
Nobuo Ikekawa, Ph.D. Director of Research
Professor Department of Macromolecular
Department of Science and Biology
Engineering Centre National de Recherche
lwaki Meisei University Scientifique URA 09
lwaki, Japan Paris, France
Tiiu Ojasoo, M.A. Richard E. Thomas, Ph.D.
Personal Assistant Associate Professor
Department of Innovation Department of Pharmacy
Roussel-Uclaf The University of Sydney
Paris, France Sydney, Australia
Zdenek Perina, Ph.D.
Zoltan Tuba, Ph.D.
Research Scientist
Department Head
Research Institute of
Research Laboratory of Organic
Pharmacology and Biochemistry
Chemistry
Prague, Czechoslovakia
Chemical Works of
G. Richter Ltd.
Jean-Pierre Raynaud, Ph.D.
Budapest, Hungary
President
Aribio
Paris, France
Irena Urbankova, Ph.D.
Information Scientist
Cecil H. Robinson, Ph.D.
Science Information Department
Professor
Research Institute of Pharmacy
Department of Pharmacology and
and Biochemistry
Molecular Sciences
Prague, Czechoslovakia
Johns Hopkins University School
of Medicine
Baltimore, Maryland William K. Wilson, Ph.D.
Assistant Director
George J. Schroepfer, Jr., Laboratory of Basic Medical
M.D., Ph.D. Science
Professor Department of Biochemistry
Departments of Biochemistry and and Cell Biology
Cell Biology and of Chemistry Rice University
Rice University Houston, Texas
Houston, Texas
S. Stoney Simons, Jr., Ph.D. Takao Yokota, Ph.D.
Chief Professor
Steroid Hormones Section Department of Biosciences
National Institutes of Health Teikyo University
Bethesda, Maryland Utsunomiya, Japan
TABLE OF CONTENTS
Chapter 1
Steroid Structure and Function from X-Ray
Crystallographic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
William L. Duax
Chapter 2
1H and 13C NMR Spectroscopy of Sterols ................................ 33
William K. Wilson and George J, Schroepfer, Jr.
Chapter 3
Theoretical Investigations on Steroid Structure and Quantitative
Structure-Activity Relationships .......................................... 91
Martin Bohl
Chapter 4
Two Approaches to Structure-Activity Relationships in the
Field of Sex Steroids and Their Analogs ................................ 157
Tiiu Ojasoo, Jean-Christophe Don~, Jean-Paul Mornon, and
Jean-Pierre Raynaud
Chapter 5
Stilbestrol Estrogens: Molecular/Structural Probes for
Understanding Estrogen Action .......................................... 209
Kenneth S. Korach
Chapter 6
Aromatase: Mechanism and Inhibition ................................... 229
Philip A. Cole and Cecil H. Robinson
Chapter 7
Structure-Activity Relationships of Glucocorticoids: Importance
of the Regulated Gene and Trans-Acting Factors in
Determining Glucocorticoid and Antiglucocorticoid Activity ............ 259
S. Stoney Simons, Jr.
Chapter 8
Molecular Structure and Biological Activity of Vitamin D
Metabolites and Their Analogs .......................................... 293
Nobuo Ikekawa and Seiichi lshizuka
Chapter 9
Molecular Structure and Biological Activity of Brassinolide and
Related Brassinosteroids ................................................. 317
Takao Yokota and Kenji Mori
Chapter 10
Structure-Activity Relationships of Androgens and Anabolics ........... 341
Irena Urbankova, Zdenek Perina, and Oldfich Hanc
Chapter 11
Structure-Activity Relationships of Steroidal Neuromuscular
Blocking Agents ......................................................... 359
Zoltan Tuba and Sandor Maho
Chapter 12
Molecular Biology of Cardiotonic Steroids .............................. 399
Richard E. Thomas
Index .................................................................... 465
1
Chapter 1
STEROID STRUCTURE AND FUNCTION FROM X-RAY
CRYSTALLOGRAPHIC STUDIES
William L. Duax
TABLE OF CONTENTS
I. Introduction ........................................................ 2
II. Progesterone Side-Chain Conformational Analysis ................. 2
III. 4-en-3-one A-Ring Conformation .................................. 7
IV. Steroid Molecular Structure, Receptor Binding, and
Hormone Action .................................................. 10
A. Estrogen Receptor Binding and Activity ................... 10
B. Progesterone Receptor Binding and Activity .............. 13
C. Corticoid Receptor Binding and Activity .................. 16
D. Androgen Receptor Binding and Activity ................. 16
V. Steroid-Protein Interactions and Binding .......................... 17
A. Enzyme Structure and Active Site Architecture ........... 17
B. Steroid-Binding Proteins ................................... 21
C. Receptor Structure and Steroid Function .................. 23
VI. Summary ......................................................... 25
References ................................................................ 26
