Medications Development: Drug Discovery, Databases, and Computer-Aided Drug Design, 134

298 Pages·2002·2.97 MB·English

National Institute on Drug Abuse
RESEARCH
MONOGRAPH SERIES
Medications
Development:
Drug Discovery,
Databases, and
Computer-Aided
Drug Design
134
U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health
Medications Development:
Drug Discovery, Databases,
and Computer-Aided Drug
Design
Editors:
Rao S. Rapaka, Ph.D.
Richard L. Hawks, Ph.D.
NIDA Research Monograph 134
1993
US. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, MD 20657
ACKNOWLEDGMENT
This monograph is based on the papers and discussions from a technical
review on “Medications Development: Drug Discovery, Databases, and
Computer-Aided Drug Design” held on November 14-16, 1991, in Washington,
DC. The technical review was sponsored by the National Institute on Drug
Abuse (NIDA).
COPYRIGHT STATUS
NIDA has obtained permission from the copyright holders to reproduce certain
previously published material as noted in the text. Further reproduction of this
copyrighted material is permitted only as part of a reprinting of the entire
publication or chapter. For any other use, the copyright holder’s permission
is required. All other material in this volume except quoted passages from
copyrighted sources is in the public domain and may be used or reproduced
without permission from the Institute or the authors. Citation of the source is
appreciated.
Opinions expressed in this volume are those of the authors and do not
necessarily reflect the opinions or official policy of the National Institute on Drug
Abuse or any other part of the US. Department of Health and Human Services.
The U.S. Government does not endorse or favor any specific commercial
product or company. Trade, proprietary, or company names appearing in this
publication are used only because they are considered essential in the context
of the studies reported herein.
NIDA Research Monographs are indexed in the “Index Medicus.” They are
selectively included in the coverage of “American Statistics Index,” “BioSciences
Information Service,” “Chemical Abstracts,” “Current Contents,” “Psychological
Abstracts,” and “Psychopharmacology Abstracts.”
National Institute on Drug Abuse
NIH Publication No. 93-3638
Printed 1993
ii
Contents
Page
Strategies for Drug Discovery 1
Michael Williams
Mass Ligand-Binding Screening Strategies for Identification
of Leads for New Drug Discovery 37
Ronald M. Burch
Antibody- and Peptide Structure-Based Drug Design 46
Manfred E. Wolff
The Use of Cloned Human Receptors for Drug Design 56
Paul R. Hartig
Synthetic Peptide Combinatorial Libraries May Be Used
To Determine Peptide Ligands for Opioid Receptors 66
Richard A. Houghten and Colette T. Dooley
Preparation of Large Peptide Libraries With One Peptide per
Bead and Their Use for the Discovery of Peptides That Bind
to Acceptors 75
Victor J. Hruby, Kit S. Lam, Michal Lebl, Wieslaw Kazmierski,
Evan M. Hersh, and Sydney E. Salmon
Computer Design of Bioactive Compounds Based on
3-D Properties of Ligands 64
Y.C. Martin
iii
Toward the Design of New Inhibitors: A Computer
Modeling Approach 103
Carlos H. Faerman
Efforts To Improve the Utilization of Protein Sequence
and Structure Databases 114
Nagarajan Pattabiraman and Krishnan Namboodiri
Use of Computer Graphics in Drug Design 129
G. W.A. Milne and M.C. Nicklaus
Purification and Cloning of Opioid Receptors 146
Ling-Yuan Li, Ying-Fu Su, Zeng-Ming Zhang,
Chih-Shung Wong, and Kwen-Jen Chang
Computer-Assisted Design of Dopamine Transporter Ligands 165
Gilda H. Loew, Hugo 0. Villar, Patricia A. Maguire,
and M. Frances Davies
The Pharmacophore for Opioid Activity 178
Mark Froimo witz
The Molecular Basis of Opioid Potency and Selectivity:
Morphiceptins, Dermorphins, Deltorphins, and Enkephalins 195
Murray Goodman, Seonggu Ro, George Ösapay,
Toshimasa Yamazaki, and Alexander Polinsky
Molecular Determinants of Cannabinoid Activity: Toward
the Design of Cannabinoid Analgesics With Reduced
Psychoactive Liability 210
Patricia H. Reggio
Cocaine Receptor: A Structure-Activity Relationship Study 229
F. Ivy Carroll, Anita H. Lewin, Michael J. Kuhar,
and John W. Baja
The Use of Conformational Restriction and Molecular
Modeling Techniques in the Development of Receptor-
Specific Opioid Peptide Agonists and Antagonists 236
Peter W. Schiller, Thi M.-D. Nguyen, Grazyna Weltrowska,
Nga N. Chung, Carole Lemieux, Brian J. Marsden,
and Brian C. Wilkes
iv
Probes for the Cannabinoid Sites of Action 253
Alexandros Makriyannis
A Model for the Structural Basis of -Opiloid Receptor Selectivity 266
Henry I. Mosberg and Frank Porreca
List of NIDA Research Monographs 281
v

FOREWORD
We are at a point in the development and application of new technologies in
medications development that is expanding at an incredible rate. This meeting
brings together the various disciplines associated with new drug design, all of
which make use of cutting edge technologies.
Receptor characterization through computer modeling techniques and the
cloning and application of such clones in in vitro screening is greatly advancing
the power of discovery programs for new pharmacotherapies. New modeling
techniques, in particular the new means to use theoretical models as a basis
for rapidly searching large 3D SAR databases for the discovery of
pharmacophoric entities among previously synthesized compounds, is an area
of technological advancement that changes almost on a daily basis. These
changes are being spurred by rapidly decreasing costs and increasing
sophistication in the hardware and software available.
Another new technological area of rapid growth is the mass synthesis and
screening of peptides, where thousands of unique peptide structures can be
prepared, screened, and new active individual peptides identified in a very short
time. These techniques in combination with receptor clones, themselves
resulting from characterization based on ligands prepared with new modeling
techniques, are rapidly altering the way we search for new pharmacotherapies,
both in the drug abuse area and in the pharmaceutical industry in general.
Limited resources can now be focused in a discovery approach that is much
more effective and efficient than was ever conceived of a decade ago.
This monograph provides an overview of some of these new techniques and
approaches, particularly as they apply to pharmacotherapeutic development for
drug abuse, and will hopefully serve to stimulate new ideas and their
application and integration in the effort to solve the drug abuse problem.
Charles Grudzinskas, Ph.D.
Director, Medications Development
Division
National Institute on Drug Abuse
National Institutes of Health
vii

Strategies for Drug Discovery
Michael Williams
INTRODUCTION
From vaccines that have reduced many fatal diseases to the realm of history,
to psychoactive agents that have permitted many people to live normal lives,
to antihypertensive drugs that prolong and improve the quality of life, to
contraceptives that have permanently changed sexual mores, the products of
the ethical pharmaceutical industry have had a major and irrevocable impact
on the social fabric of society. Yet many disease states still remain untreated
or are currently treated by agents whose side-effect profile leaves significant
cause for concern. The aging of the population, partly a result of the availability
of more effective medications, has presented additional challenges in
therapeutic agent development, with an urgent need for drugs to treat
arthritis, cancer, neurodegeneration, and cognition impairment.
However, the process of drug discovery is complex and costly (Jack 1989;
DiMasi et al. 1991), and innovative science is especially so. But drug
discovery is more than the application of basic research knowledge and
technologies (Black 1986); it involves many facets of project management
and focus (Klimstra and Rafael 1992; Roussel et al. 1991; Jacques et al.
1992). To precisely define the drug discovery process and the parameters
crucial to success is a difficult task. For each successful drug there are many
accounts, both corporate and scientific, as to the process and the visionaries
and facilitators involved in bringing the compound to the marketplace.
Overviews of the drug research and development (R&D) processes (Sneader
1985, 1986; Williams and Malick 1987; Hesp and Resch 1987; Spilker 1988;
Hamner 1990; deStevens 1991; Gilbert 1992) have been complemented by
insightful case studies for several important drugs (Maxwell and Eckhardt
1990). Given the proprietary nature of the drug discovery process, the
failures, the blind alleys, and the persistence that are such an important
part of the drug discovery environment and that can account for up to 80
percent of the corporate research effort are rarely documented. Thus, the
database from which to derive lessons that may aid in the implementation of
new projects is limited. The commercial focus of the drug discovery process
equates the success of a project with a product and rarely with the successful
testing of a hypothesis (via the use of a new compound) that results in the
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