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

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National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Medications Development: Drug Discovery, Databases, and Computer-Aided Drug Design U.S. Department of Health and Human Services1 • Public3 Health Service4 • 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 1 advancement of scientific knowledge. Given that discovery is a process of “learning things not already known” (Roussel et al. 1991), success is equally tenable when a project is terminated for technical or competitive reasons, resulting in the avoidance of further “sunk costs” (Staw and Ross 1989). In this chapter, some integral elements of the drug discovery process are discussed, focusing on newer technologies and the scientific
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