`
`Also available as a printed book see title verso for ISBN details
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`Textbook of Drug Design and Discovery
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`Textbook of Drug Design and
`Discovery
`
`Third edition
`
`Povl Krogsgaard-Larsen,
`Tommy Liljefors and
`Ulf Madsen
`
`London and New York
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`First published 2002
`by Taylor & Francis
`11 New Fetter Lane, London EC4P 4EE
`Simultaneously published in the USA and Canada
`by Taylor & Francis Inc,
`29 West 35th Street, New York, NY 10001
`
`Taylor & Francis is an imprint of the Taylor & Francis Group
`This edition published in the Taylor & Francis e-Library, 2005.
`
`To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection
`of thousands of eBooks please go to www.eBookstore.tandf.co.uk.
`
`© 2002 Povl Krogsgaard-Larsen
`All rights reserved. No part of this book may be reprinted or reproduced
`or utilised in any form or by any electronic, mechanical, or other means,
`now known or hereafter invented, including photocopying and recording,
`or in any information storage or retrieval system, without permission in
`writing from the publishers.
`British Library Cataloguing in Publication Data
`A catalogue record for this book is available from the British Library
`Library of Congress Cataloging in Publication Data
`A catalog record for this book has been requested
`
`ISBN 0-203-30137-4 Master e-book ISBN
`
`ISBN 0-203-34560-6 (Adobe e-Reader Format)
`ISBN 0-415-28287-X (Print Edition) HB
`ISBN 0-415-28288-8 (Print Edition) PB
`
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`Contents
`
`List of contributors
`Preface
`
`1 Drug design and discovery: an overview
`LESTER A.MITSCHER
`
`2 Role of molecular recognition in drug design
`PETER ANDREWS AND MICHAEL DOOLEY
`
`3 Stereochemistry in drug design
`IAN J.KENNEDY AND DAVID E.JANE
`
`4 Computer-aided development and use of three-dimensional pharmacophore
`models
`TOMMY LILJEFORS AND INGRID PETTERSSON
`
`5 Quantitative structure-activity relationships and experimental design
`ULF NORINDER AND THOMAS HÖGBERG
`
`6 Receptors: structure, function and pharmacology
`HANS BRÄUNER-OSBORNE
`
`7 Ion channels: structure, function and pharmacology
`DAVID J.TRIGGLE
`
`8 Radiotracer: synthesis and user in imaging
`CHRISTER HALLDIN AND THOMAS HÖGBERG
`
`9 Excitatory and inhibitory amino acid receptor ligands
`ULF MADSEN AND BENTE FRØLUND
`
`vii
`xii
`
`1
`
`37
`
`57
`
`93
`
`127
`
`171
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`191
`
`229
`
`259
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`10 Acetylcholine and histamine receptors and receptor ligands: medicinal
`chemistry and therapeutic aspects
`POVL KROGSGAARD-LARSEN AND KARLA FRYDENVANG
`
`11 Dopamine and serotonin receptor and transporter ligands
`KLAUS P.BØGESØ AND BENNY BANG-ANDERSEN
`
`12 Enzymes and enzyme inhibitors
`ROBERT A.COPELAND AND PAUL S.ANDERSON
`
`13 Metals in medicine: inorganic medicinal chemistry
`OLE FARVER
`
`14 Design and application of prodrugs
`CLAUS S.LARSEN AND JESPER ØSTERGAARD
`
`15 Peptides and peptidomimetics
`KRISTINA LUTHMAN AND ULI HACKSELL
`
`16 Classical antiviral agents and design of new antiviral agents
`PIET HERDEWIJN AND ERIK DE CLERCQ
`
`17 Anticancer agents
`INGRID KJØLLER LARSEN AND JETTE SANDHOLM KASTRUP
`
`Index
`
`305
`
`336
`
`378
`
`408
`
`460
`
`515
`
`545
`
`573
`
`625
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`Contributors
`
`Anderson, Paul S.
`Chemical and Physical Sciences R&D
`Bristol-Myers Squibb Company
`P.O. Box 80500
`Wilmington
`DE 19880–0500
`USA
`
`Andrews, Peter
`Centre for Drug Design and
`Development
`The University of Queensland
`Brisbane
`Queensland 4072
`Australia
`
`Bang-Andersen, Benny
`H.Lundbeck A/S,
`Department of Medicinal
`Chemistry
`9, Ottiliavej
`DK-2500 Valby
`Denmark
`
`Bøgesø, Klaus P.
`H.Lundbeck A/S
`9, Ottiliavej
`DK-2500 Valby
`Denmark
`
`Bräuner-Osborne, Hans
`Royal Danish School of Pharmacy,
`Department of Medicinal Chemistry
`2, Universitetsparken,
`DK-2100 Copenhagen Ø
`Denmark
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`Copeland, Robert A.
`Chemical Enzymology
`Bristol-Myers Squibb Company
`P.O. Box 80400
`Wilmington
`DE 19880–0400
`USA
`
`De Clercq, Erik
`Rega Institute
`Katholieke Universiteit Leuven
`10, Minderbroedersstraat
`B-3000 Leuven
`Belgium
`
`Dooley, Michael
`Centre for Drug Design
`and Development
`The University of Queensland
`Brisbane
`Queensland 4072
`Australia
`
`Farver, Ole
`Royal Danish School of Pharmacy
`Department of Analytical and
`Pharmaceutical Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Frølund, Bente
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Frydenvang, Karla
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
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`Denmark
`
`Hacksell, Uli
`Acadia Pharmaceuticals Inc.
`3911 Sorrento Valley Blvd.
`San Diego
`CA 92121–1402
`USA
`
`Halldin, Christer
`Department of Clinical NeuroScience
`Psychiatry Section
`Karolinska Hospital
`S-17176 Stockholm
`Sweden
`
`Herdewijn, Piet
`Rega Institute
`Katholieke Universiteit Leuven
`10, Minderbroedersstraat
`B-3000 Leuven
`Belgium
`
`Högberg, Thomas
`7TM Pharma A/S
`2, Rønnegade
`DK-2100 Copenhagen
`Denmark
`
`Jane, David E.
`Department of Pharmacology
`School of Medical Sciences
`University of Bristol
`University Walk
`Bristol BS8 1TD
`UK
`
`Kastrup, Jette Sandholm
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
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`Kennedy, Ian J.
`Department of Pharmacology
`School of Medical Sciences
`University of Bristol
`University Walk
`Bristol BS8 1TD
`UK
`
`Krogsgaard-Larsen, Povl
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Larsen, Claus S.
`Royal Danish School of Pharmacy
`Department of Analytical and
`Pharmaceutical Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Larsen, Ingrid Kjøller
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Liljefors, Tommy
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Luthman, Kristina
`Göteborg University
`Department of Chemistry
`Medicinal Chemistry
`S-412 96 Göteborg
`Sweden
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`Madsen, Ulf
`Royal Danish School of Pharmacy
`Department of Medicinal Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Mitscher, Lester A.
`University of Kansas
`School of Pharmacy
`Department of Medicinal Chemistry
`Lawrence, Kansas 66047–2101
`USA
`
`Norinder, Ulf
`AstraZeneca R&D
`Discovery
`Medicinal Chemistry
`S-15185 Södertälje
`Sweden
`
`Østergaard, Jesper
`Royal Danish School of Pharmacy
`Department of Analytical and
`Pharmaceutical Chemistry
`2, Universitetsparken
`DK-2100 Copenhagen Ø
`Denmark
`
`Pettersson, Ingrid
`Novo Nordisk A/S
`Novo Nordisk Park G8
`DK-2760 Måløv
`Denmark
`
`Triggle, David J.
`University at Buffalo
`State University of New York
`415 Capen Hall
`Buffalo
`NY 14260–1608
`USA
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`Preface
`
`The field of medicinal chemistry and drug design is in a state of swift development and is
`at present undergoing major restructuring. The molecular biological revolution and the
`progressing mapping of the human genome have created a new biochemical and
`biostructural ‘world order’. These developments have provided new challenges and
`opportunities for drug research in general and for drug design in particular. The major
`objectives of the medicinal chemists are transformation of pathobiochemical and—
`physiological data into a ‘chemical language’ with the aim of designing molecules
`interacting specifically with the derailed or degenerating processes in the diseased
`organism.
`Potential therapeutic targets are being disclosed with increasing frequency, and this
`exponential growth will continue during the next decades. In this situation, there is a need
`for rapid and effective target validation and for accelerated lead discovery procedures.
`Consequently, most industrial medicinal chemistry laboratories have built up new
`technologies in order to meet these demands. Key words in this regard are construction of
`compound libraries, high or ultrahigh through-put screening, accelerated ADME and
`toxicity tests, and automatized cellular assay systems.
`In parallel with this development, biostructure-based drug design and intelligent
`molecular mimicry or bioisosterism are areas of growing importance in the medicinal
`chemistry ‘playing field’. Structural biology is becoming an increasingly important part
`of molecular biology and biochemistry, and, furthermore, organic chemists are
`increasingly directing their attention towards synthetic aspects of biomolecules and
`biologically active compounds biosynthesized by plants and animals. Thus the borderland
`between biology, biochemistry, and chemistry is rapidly broadening and is becoming the
`most fruitful working field for innovative and intuitive drug design scientists.
`Where are the academic medicinal chemistry and drug design departments in this area
`of drug research, which is moving towards an increasing degree of integration of
`scientific disciplines? Furthermore, how should medicinal chemistry
`teaching
`programmes be organized and taught in this highly dynamic research area? These burning
`questions need to be effectively addressed. In order to attract the attention of intelligent
`students, the creative and fascinating nature of drug design must be the underlying theme
`of basic and advanced student courses in medicinal chemistry. In relation to industrial
`screening programmes and ‘hitfinding’ procedures, students should be taught that the
`conversions of ‘hits’ into lead structures and further into drug candidates require
`advanced synthetic chem¬ istry supported by computational chemistry. Furthermore,
`these medicinal chem¬
`istry approaches should be
`integrated with molecular
`pharmacology studies using cloned target receptors, ion channels, or enzymes, expressed
`in appropriate model systems.
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`It is beyond doubt that a steadily increasing number of biomolecules will be subjected
`to X-ray crystallographic structural analysis. The number of enzymes with established
`three-dimensional structure is now increasing exponentially, and this growth will
`continue during the next decades. Even oligomeric membranebound receptors can now be
`crystallized and subjected to X-ray crystallographic analysis, but such analyses of mono-
`or oligomeric receptors are still hampered by major experimental difficulties. In recent
`years, however, biostructural scientists have succeeded in crystallizing recombinant
`versions of the binding domains of a G protein-coupled receptor as well as a ligand-gated
`ion channel. Structural analyses of these binding domains co-crystallized with agonist
`and antagonist ligands have already provided insight into the structural basis of receptor-
`ligand interactions and of receptor activation and blockade.
`These breakthroughs in biostructural chemistry have opened up new avenues in drug
`information derived from X-ray analyses of enzymeinhibitor
`design. Structural
`conglomerates has been and continues to be very valuable for the design of new types of
`inhibitors. Similar pieces of information derived from studies of receptor binding
`domains co-crystallized with different types of competitive or noncompetitive ligands
`undoubtedly will be of key importance in receptor ligand design projects. These
`approaches which are in the nature of drug design on a rational basis will become
`important parts of student teaching programmes in medicinal chemistry.
`In academic research and teaching, biologically active natural products probably will
`play a progressively important role as lead structures. Not only do such compounds often
`possess novel structural characteristics, but they also frequently exhibit unique biological
`mechanisms of action, although naturally occurring ‘toxins’ typically show nonselective
`pharmacological effects. By systematic structural modification, including molecular
`mimicry approaches, it has been possible to ‘tame’ such ‘toxins’ and convert them into
`leads with specific actions on biofunctions of key importance in diseases. Biologically
`active natural products undoubtedly will continue to be important starting points for
`academic drug design projects, and such approaches will continue to be exciting case
`stories in student medicinal chemistry courses.
`In this third edition of the textbook, all of these aspects of academic and industrial
`medicinal chemistry and drug design are dealt with in an educational context.
`Povl Krogsgaard-Larsen
`Tommy Liljefors
`Ulf Madsen
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`Chapter 1
`Drug design and discovery: an overview
`Lester A.Mitscher
`
`1.1 INTRODUCTION
`
`Drugs are chemicals that prevent disease or assist in restoring health to diseased
`individuals. As such they play an indispensable role in modern medicine.
`Medicinal chemistry is that branch of science that provides these drugs either through
`discovery or through design. The classical drugs of antiquity were primarily discovered
`by empirical observation using substances occurring naturally in the environment. In the
`last two centuries, drugs increasingly were also prepared by chemical alteration of natural
`substances. In the century just past many novel drugs were discovered entirely by
`chemical synthesis. An ever increasing understanding of the nature of disease, how cells
`work, and how drugs influence these processes has in the last two decades led
`increasingly to the deliberate design, synthesis and evaluation of candidate drug
`molecules. In the third millennium, all of these techniques are in use still and the student
`of drug design and development must appreciate their relative value. Added to this
`picture are novel opportunities made possible by deeper understanding of cell biology
`and genetics.
`Contemporary medicinal chemistry draws upon many disciplines so that its students
`and practitioners must have a broad working knowledge above all of organic chemistry
`but in addition, the student must be comfortable with significant elements of
`biochemistry, molecular biology, pharmacology, neurobiology, toxicology, genetics, cell
`biology, biophysics, quantum mechanics, anatomy, physiology, pathology, clinical
`medicine, computer technology, and the like. This is a tall but manageable order.
`The central objective of each branch of chemistry is to possess such an understanding
`of the relationship between chemical structure and molecular properties that given a set
`of desired characteristics, a molecule can be proposed and prepared that should come
`close to possessing them. Next should follow, without undue experimentation, a testing
`and molecular refining cycle until a satisfactory molecular solution to the problem is at
`hand. A mature chemical science is efficient in achieving these characteristics. The reader
`will readily appreciate the complexity of the task in the case of medicinal chemistry and
`that the subject is still adolescent. A daunting feature is the number of properties that a
`candidate substance must possess in order to function therapeutically in the human body
`and so to become a drug. We also have much to learn about pathophysiology. Despite all
`this, a remarkable range of pharmaceuticals has been developed successfully and the pace
`of new entity introduction is gratifyingly rapid.
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`Textbook of drug design and discovery 2
`This textbook describes the manner in which medicinal chemists utilize the various
`fields upon which they draw and the specific stratagems that they employ to advance
`promising molecules into clinical use for the alleviation of disease and the betterment of
`mankind. This chapter is intended to introduce briefly some important topics not covered
`significantly elsewhere in this book and to provide a contextual framework especially for
`those comparatively new to the study of drug seeking.
`
`1.2 HISTORICAL PERSPECTIVE
`
`From prehistoric times until well into the twentieth century the vast majority of organic
`drugs originated from natural materials, often in crude mixtures. In early times, there was
`no possibility of understanding the nature of disease. Rather discoveries were made and
`preserved based upon observations of natural phenomena and the consequences of
`consumption of materials that alleviated distress. Of necessity, progress was disjointed
`and empirical. The use of opium, licorice, ephedra, marijuana, camellia, alcohol, digitalis,
`coca, quinine and a host of others still in use long predates the rise of modern medicine. It
`is interesting to note that the uses of these materials often are for diseases that are chronic
`and prevalent and are based upon responses that are observable in healthy individuals.
`These natural products are surely not elaborated by plants for our therapeutic
`convenience. We believe that they have survival value for the plants in dealing with their
`own ecological challenges and that only a small subset are found to have activity that can
`be co-opted for human or animal chemotherapy.
`About 100 years ago, the mystery of why only certain molecules produced a specific
`therapeutic response was satisfactorily rationalized by the idea of Langley and Ehrlich
`that only certain cells contained receptor molecules that served as hosts for the drugs. The
`resulting combination created a new super molecule that had characteristically new
`properties producing a response of therapeutic value. One extension of this view was that
`the drug was a key that fit the target specifically and productively like a corresponding
`lock. When the fit was appropriate, a positive (agonist) pharmacological action followed
`analogous to opening a door. In other cases, a different kind of fit blocked the key so that
`the naturally intended key could not be inserted and antagonist action resulted so that the
`figurative door could not be opened. Thus, if one had found adventitiously a ligand for a
`receptor, one could refine its fit by opportunistic and systematic modification of the
`drug’s chemical structure until it functioned very well. This productive idea hardly
`changed for the next half century and assisted in the preparation of many useful drugs. A
`less fortunate corollary of this useful picture is that it led to some restriction of
`imagination in drug design. The drug and its receptor (whose molecular nature was
`unknown when the theory was promulgated) were each believed to be rigid molecules
`precrafted to fit one another precisely. Most commonly, receptors are transmembranal
`glycoproteins accessible from the cell surface whose drug compatible region contains
`certain specific amino acids arranged in 3D-space.
`Since the receptor surface is chiral, it is not surprising that chirality in the drug
`structure often plays an important role in cellular responses. This important topic is the
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`Drug design and discovery: an overview 3
`subject of Chapter 3. Predicting an optimal ligand fit from structure-activity data through
`mathematical analytical methods is the subject of Chapter 5. These receptor surfaces are
`often present in molecular clefts such that they create a special local environment that is
`somewhat protected from the bulk solvent but accessible to substances present in it. The
`intricacies of interactions in this special environment is treated in Chapter 2. The active
`site is assembled from non-adjacent amino acid residues as a consequence of the 3D
`folding of the protein. Non-covalent bonds are formed with the appropriate ligand that
`that usually signals other
`indeed produce a
`temporary new macromolecule
`macromolecules deeper in the cell that satisfactory occupancy has taken place and the
`cell responds to this signal by taking the appropriate action.
`Further complexities are uncovered continually. For example, a number of receptors
`are now known that consist of clusters of proteins either preassembled or assembled as a
`consequence of ligand binding. The component macromolecules can either be homo- or
`heterocomplexes. The complexity of finding specific ligands for systems of this
`complexity readily can be imagined (Milligan and Rees 2000).
`The main modern difference from the classical picture, other than identifying
`specifically the chemical nature of the receptor and how it interacts with its ligand, is the
`realization that neither drug nor receptor need to be rigid. The opposite extreme to lock
`and key is the zipper model. In this view, a docking interaction takes place (much as the
`end of a zipper joins the talon piece) and, if satisfactory complementarity is present, the
`two molecules progressively wrap around each other and accommodate to each others
`steric needs. The reader will appreciate that all possible intermediate cases (rigid
`drug/flexible receptor; flexible drug/rigid receptor, etc.) are now known. A consequence
`of this mutual accommodation is that knowledge of the ground state of a receptor may
`not be particularly helpful when it adjusts its conformation to ligand binding. Thus, in
`many cases one now tries to determine the 3D aspects of the receptor-ligand complex. In
`those cases where X-ray analysis remains elusive, modeling the interactions involved is
`appropriate. This is the subject of Chapter 4. Further details of this marvelously complex
`system are presented in Chapter 6.
`Earlier it was also noted that enzymes could be modulated for pharmacological benefit.
`Enzymes share many characteristics with glycoprotein receptors except that they assist in
`the performance of chemical reactions on their substrates so that the interaction is
`intrinsically more information rich than is the receptor-ligand interaction (which leaves
`the ligand unchanged). Until very recently, it was usually only possible to inhibit enzyme
`action rather than to promote it. Disease frequently results from excessive enzymatic
`action so selective inhibition of these enzymes is therapeutically useful. These
`interactions are covered in Chapter 12.
`Much later it was discovered that other classes of receptors existed. For example, the
`highly lipophilic steroid hormones are able to cross the cell membrane and find their
`receptors in the cytoplasm. Receptor occupation is followed by migration of the new
`complex into the nucleus followed by selective gene activation. A third class of receptors
`consists of clusters of proteins assembled such as to create a specific transmembranal
`central pore. This channel permits the selective directional passage of specific ions in or
`out of the cell. These ion channels can be ion ligated or current sensitive. The ion flux
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`Textbook of drug design and discovery 4
`creates a current that signals for the performance of specific work by the cell. New
`information involving this complex communication system appears almost daily. Chapter
`7 discusses this field.
`Over time, it became apparent that DNA and RNA also can be receptors and that the
`technology needed in order to design ligands for these macromolecules differs in detail
`from that needed to design ligands for receptors. The earliest applications of DNA
`liganding lie in inhibiting its formation and function so that cell death was the expected
`result. Since rapid uncontrolled cell growth is characteristic of cancer, this sort of
`methodology, starting in about 1940, led to the first successful chemical treatments of
`this dreaded disease. Revolutionary treatments for cancer are within our grasp based upon
`novel discoveries in cell biology and genomics. This will be presented in detail in
`Chapter 17.
`Much greater therapeutic safety attends inhibition of the enzymes that are involved in
`DNA synthesis and its processing. This has led to recent remarkable advances in the
`chemotherapy of viral diseases. Until quite recent times, viral diseases were extremely
`difficult to treat but this picture has now changed remarkably as will be described in
`Chapter 16.
`RNA is responsible for the biosynthesis of proteins and use of species specific
`inhibitory ligands for it results in cell death or stasis. This phenomenon is responsible for
`the therapeutically useful selective toxicity of many antibiotics.
`Interestingly, until the mid 1970s known drug targets were primarily neurotransmitter
`receptors on cell surfaces. Since that time, a wealth of information has been uncovered
`and many other choices are now available. In this context, it is interesting therefore to
`consider the molecular targets for which drugs are contemporarily crafted even though
`this is shifting rapidly (Drews 2000):
`
`1 Cellular receptors
`2 Enzymes
`3 Hormones and factors
`4 Ion channels
`5 DNA
`6 Nuclear receptors
`7 Unknown
`
`45%
`28%
`11%
`5%
`2%
`2%
`7%
`
`Clearly, cellular receptors and enzymes make up the bulk of the targets favored at this
`time.
`That it took so long to work out the details that we presently understand about drug
`action is not surprising. When the receptor theory was first advanced, no protein structure
`would be known for at least 50 years on. Furthermore, in contrast to enzymes, the
`receptor binds the ligand with temporary non-covalent bonds and does not process its
`ligand. Thus, one could only infer what intermolecular forces were operating and what
`could be the molecular and biological consequences of the interaction. Striking advances
`in molecular spectroscopy have led to the identification of the 3D-structure of many
`enzymes and their substrates and inhibitors and, indeed, for a few receptors and their
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`Drug design and discovery: an overview 5
`ligands. Increasingly nuclear magnetic resonance methods are also producing detailed
`structural information. The use of computer graphic techniques allows for virtual
`screening of candidates for synthesis. By this, a given ligand can be subtracted from a
`3D-picture of a drug ligand interaction and a new ligand can be fitted in instead. If
`suggestive, the new ligand can be synthesized and tested. It is also possible to screen
`actually or virtually through a collection of available molecules to find substances that
`will fit into the active site in place of a known ligand and then to test it for efficacy. The
`methodology is still empirical but the time investment is machine time rather than
`synthesis time so, aside from the cost of the machinery and the development of the
`sophisticated software, time is saved.
`Even this complex picture is greatly simplified. It is now well recognized that most
`receptors exist as families of subreceptors and that further specificity of action results
`from ligands that occupy only a specific one of the subreceptors and not the others. Doing
`this effectively became widely practiced from about 1965. A well-known example of this
`that illustrates the concept is that norepinephrine exerts a variety of effects in the body by
`virtue of its occupying all three of the families of adrenergic sub receptors (Figure 1.1).
`Further complexities arise from there being many subclasses of receptors within each
`family. Each of these has its own structural requirements. The body deals with this
`problem by secreting this neurotransmitter near a specific type of receptor so as to get a
`specifically desired response and then either destroying the transmitter promptly or
`reabsorbing it and putting it back into storage for future use once the stimulus that led to
`neurotransmitter release is over. An added virtue of this means of action is that the action
`of the drug is temporary so that it has a start point and a stop point of satisfactory length
`and that it does not migrate far away to occupy unintended receptors and so produce side
`actions. Through molecular manipulation, specific agonists and antagonists have been
`prepared for all of these adrenergic subreceptors (Figure 1.1). Thus, through creative
`analoging fine control of the specific pharmacological response can be obtained.
`The devilish complexity of the process of drug design and development will be readily
`appreciated by considering also that the processes just described deal only with potency
`and
`selectivity.
`Suitable
`toxicological,
`pharmacokinetic,
`pharmacodynamic,
`pharmaceutical and commercial factors must also be built into the substance before
`marketing can take place.
`Even with the advantage of all this accumulated knowledge it is certain that a great
`many molecules must be investigated before a marketable version can be found. It is
`estimated that in 1997 about US$6 billion were spent worldwide on screening
`technologies and about 100000 compounds are screened per day. The numbers are truly
`daunting. Several million compounds must be screened in order to find a thousand or so
`that have approximately correct characteristics and only a few of these successfully
`advance through analoging and biotesting to produce a dozen agents suitable for clinical
`study. Only six of these on average progress into clinical trials and just one reaches the
`market. Those new to the field may be surprised to learn that terms implying deliberately
`rational drug design came into general acceptance only in the last 20 years! In this
`context, the view advanced at that time that X-ray and computer techniques would allow
`one to prepare only a few dozen substances before finding a marketable substance now
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`Textbook of drug design and discovery 6
`appear incredibly naive. It is clear in retrospect that the barriers represented by
`pharmacokinetic problems had been very significantly underestimated. The appeal of
`rational drug design is obvious in that it promises to reduce the empiricism of drug
`seeking enhancing the satisfaction of the practitioners and promising rapid economic
`returns to their sponsors. Fortunately, the field moves ever closer to the realization of this
`dream.
`
`Figure 1.1 Agonists and antagonists for adrenergic receptors.
`
`The pace of screening has accelerated dramatically in recent years. The application of
`high throughput screening methods has required rapid synthesis of large arrays of
`compounds suitable for screening. This in turn has led to the introduction and wide
`spread acceptance of combinatorial chemical methods.
`The remainder of this chapter and, indeed, the book will assume that the reader is
`familiar with modern synthesis and will therefore address the questions of design and
`optimization. What molecules should be made, how should they be evaluated, and how
`should they be advanced to clinical use is our topic. It is important at this stage also to
`emphasize that priority of discovery is essential not only for very valid commercial
`reasons but also because drugs relieve suffering and delay is undesirable for humanitarian
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`Drug design and discovery: an overview 7
`reasons. Thus, we rarely are able to pursue perfection. We only find it in the dictionary
`anyhow. The medicinal chemists motto is, instead, ‘good enough—soon enough’.
`
`1.3 WHAT KINDS OF COMPOUNDS BECOME DRUGS?
`
`In order to be successful, one should know what gold looks like before panning. Drug
`seeking is analogous—it is essential to have a good idea of what kind of molecules are
`likely to become successful drugs before beginning. The normally preferred means of
`administration of medicaments is oral. Whereas there are no guarantees and many
`exceptions, the majority of effective oral drugs obey the Lipinski rule of fives. The data
`upon which this rule rests is drawn from 2500 entries extracted from the US Adopted
`Names, the World Drug lists, and the internal Pfizer compound collections. There are
`four criteria:
`1 The substance should have a molecular weig