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XII Chemical Structures of Amino Acids, Molecular Graphics and Introduction
Introduction
Drug design is science, technology, and art all in one. An invention is the result of acreative act; adiscovery is the recognition of apre-existing reality. Design involves both
processes, but emphasizes afocused approach based on existing knowledge and technologies. In addition, the creativity and intuition of the researcher play acrucial role.
Drugs are all substances that exert an effect on asystem by inducing aparticular
effect. In the context of this book, they are substances that exhibit abiochemical or
pharmacological effect, in most cases as drug medications, that achieve atherapeutic
effect in humans.
The idea of rational drug design is not new. Already more than acentury ago, organic compounds were synthesized in atargeted manner in order to produce new drugs.
Scientists have always worked with models and design hypotheses. In the early days,
these models were often awed or even wrong. As our understanding of the molecular
basis of diseases has steadily improved, the models and hypotheses have become better
and more reliable. However, we are still far from the dream of designing anished drug
using rational concepts on the drawing board.
In the case of artistic design, such as aposter or acommodity, or in the case of
engineering, such as the design of acar, acomputer, or amachine, the result is usually
directly predictable. In contrast, the design of active substances is even today not sufciently predictable. The consequences of even the smallest structural changes of the
biological properties and the mode of action of abiologically active molecule are too
multifaceted and yet too poorly understood.
Until now, scientists have relied on the principle of trial and error in order to nd
new medicines. The rules empirically derived have resulted in aknowledge base for the
rational design of active substances, which individual researchers have put into practice with greater or lesser success. Today, many new methods from genetic engineering,
structural biology, biophysics, and informatics are available for the search for novel
drugs. The work of recent years has contributed above all to our understanding of the
molecular mechanisms of action of many known drugs, although these compounds
were often previously found by simpler methods and sometimes even discovered by
chance. This book attempts to present many of these modes of action or mechanisms.
Methodological advances in experimental structure determination now allow the
routine determination of the three-dimensional structure of proteins, RNAs and DNAs,
as well as their ligand complexes. As shown in many of the illustrations in this book
(see the general explanation of how to “read” these illustrations on pageX), in combination with the commented videos provided via the Internet and accessible via QR
codes, they make avery important contribution to the reader’s understanding of the
targeted design of active agents. Three-dimensional (3D) structures down to atomic
resolution are known of more than amillion small molecules and more than 200,000
proteins, nucleic acids, and protein–ligand complexes. Their number continues to grow
exponentially. Methods for predicting the spatial structures of small molecules are mature. Semiempirical and quantum chemical calculations on active agents are routinely
used. The sequencing of the human genome is complete, and new genome data from
other organisms are being added weekly.
Recently, signicant progress has been made in predicting the 3D structures of proteins from their amino acid sequence. With the help of articial intelligence, computer
programs evaluate the enormous treasure of experimentally determined structural data.
What is still lacking is acomparably powerful and detailed database that reveals the
structure of water molecules in the interior and on the surface of biomolecular complexes. Yet, their properties are essential for understanding how drugs bind and act.
Predictions of the protonation states of amino acids in protein-binding sites and of
ligand functional groups, particularly their changes during ligand binding, are still in
their infancy. The potential of RNA molecules for drug therapy is slowly being recognized. Concepts for structural–biological classication and de novo prediction of the
Chemical Structures of Amino Acids, Molecular Graphics and Introduction
XIII
spatial structures of RNA molecules, including their solvate structures and protonation
states, still need to be developed. Only then will it be possible to use machine learning
and articial intelligence to provide solutions for drug design through computer algorithms, similar to the current protein structure prediction from sequence.
The structure-based and computer-aided design of new drugs is now an integral part
of practical drug research. Thanks to adramatic increase in computing power, computer
programs now support the search, modeling, and targeted design of new active agents.
The mere increase in throughput can possibly enable these techniques to exhaustively
design and lter for potential drug candidates. However, to take the methodology to
ahigher level of reliability and relevance, adeeper understanding of drug–target interactions is essential. How do the local water structure and the mutual polarization of
the binding partners affect the biological properties? Restricting ourselves solely to the
interactions of the pharmaceuticals with the residues in the binding pocket of asingle
biological target structure also does not adequately capture the complexity of drug action. The binding kinetics and residence time of adrug at its target structure are just as
important as pharmacokinetic, toxicological, and metabolic properties. How important
are modulations of the dynamics of the formed complexes for drug action and therapeutic success? What other target structures are inuenced in addition to the actual target?
How troublesome, or perhaps even how important, are adverse side effects? When can
apatient be offered personalized therapy and individualized dosing? Today, the gene
sequencing of each and every one of us is possible at anancially affordable cost and
in areasonable amount of time. But how can this knowledge be used for personalized
medicine? Future drug research will have to answer these questions for patients without
losing sight of the cost–benet ratio.
So why is the development of anew drug still so complicated and why has the time
it takes hardly been reduced in the last 40years? The cost of developing and launching adrug to market has risen steadily and continues to do so. The current cost range
is between US$200 million and 4000 million. Only large pharmaceutical companies,
especially those in the top sales and prot segment, can still afford such an investment.
There is always the risk of failure in the late stages of clinical trials or of misjudging
of the therapeutic potential of anew compound. There are often enough setbacks. On
amore optimistic note is the observation that drug discovery is now tackling much
more challenging targets. Ten or twenty years ago, these were still considered inaccessible or simply “undruggable.” Examples include the successful disruption or targeted
enhancement of protein–protein contact surfaces by small molecules or the targeting of
overregulated or pathogenic proteins for selective proteolytic degradation. The body’s
own immune system is enhanced to selectively eliminate virus-infected or degenerated
cancer cells.
There is, however, acrucial hurdle to overcome when using drug molecules to interfere with the control mechanisms of biological processes: In order to compete with the
natural ligands of enzymes and receptors, or to mimic their properties, they must be
sufciently precise and efcient in terms of both the mechanism of action and the site
of action. In the case of endogenous active compounds, our organism uses different
principles. Substances such as the body’s own hormones act predominantly systemically,
meaning they are released at one site in the body and transported via the bloodstream to
one or more completely different sites of action. It is only there that they develop their
effect. This requires ahigh degree of specicity and selectivity of action. Substances
such as neurotransmitters are also used by our body in many places for very different
tasks. This can only be achieved in acontrolled manner if they are used strictly locally.
Our organism uses ahighly developed spatial compartmentalization for this purpose.
Substances such as neurotransmitters are formed close to where they are needed, where
they exert their task, and then they are immediately removed again. Drug research is
also aimed at interfering with these mechanisms and possibly correcting them, but we
want to use substances that can be taken orally if possible. As with hormones, this is
only possible if a very high specicity and selectivity can be achieved. In addition to
this, sufcient stability and bioavailability from the gastrointestinal tract must also be
XIV Chemical Structures of Amino Acids, Molecular Graphics and Introduction
achieved. Under these conditions, it is extremely difcult to achieve atailored therapeutic inuence on target structures for which the body itself uses only relatively small and
unselective ligands. Inevitably, our active agents must become larger in order to achieve
the required selectivity of binding. It is obvious that efcacy proles of such substances
will be somewhat different, and usually they will increase in size for selectivity reasons.
All these aspects open up enormous perspectives for drug development, but they do not
make it any easier today.
The purpose of this book is to describe the development of new drugs under these
difcult and ever-changing conditions. Design methods are presented, and drug development is illustrated with known mechanisms of action and selected case studies.
Drug discovery is amultidisciplinary eld in which chemists, pharmacists, physicians,
technologists, molecular biologists, biochemists, pharmacologists, toxicologists, and
clinicians work together to pave the way for acompound to become anew therapeutic
drug. For these reasons, the majority of drug developments still takes place in industry.
Only industry has the nancial resources and, above all, the organizational structures
needed for all the disciplines involved to successfully work together. Only in this way
can research be channeled in atargeted manner. However, the basic principles and
forward-looking innovations in drug research are increasingly being developed in academia, not least for reasons of cost and critical risk assessment. Interestingly, more
and more university research initiatives are focusing on the development of drugs for
infectious diseases, rare diseases, or diseases of the Third World. The inevitably commercially oriented pharmaceutical industry in the industrialized countries has increasingly
withdrawn from these areas. This is all the more alarming when one considers that our
improved quality of life and increased life expectancy are largely due to the victory
over devastating infectious diseases. The coronavirus pandemic that we have just lived
through has brought this back to our minds in avery vivid way.
Rising research and development costs, an already high standard of therapy in many
indications, much greater safety awareness and, as aresult, more stringent regulatory
requirements have led to asteady decline in the number of new chemical entities (NCEs)
introduced annually into therapy over the past few decades: from 70–100 NCEs in 1960–
1969, to 60–70 in 1970–1979, to an average of50 in 1980–1989, to 40–45 in the 1990s
and the two decades of the new millennium. However, in addition to the expansion of
indications for drugs that have been known for along time, it is the new developments
that have brought signicant progress in therapy.
Aparadigm shift is often talked about in pharmaceutical research. This refers
to the application of new technologies and knowledge. As far as the structure of
the market is concerned, the process of concentration through company takeovers,
acquisitions, and mergers into giant Big Pharma companies has slowed considerably.
Fortunately, this has given way to avery dynamic, almost unmanageable scene of
small, highly exible biotech and start-up companies that are stimulating pharmaceutical research with new, innovative strategies. Big pharmaceutical companies are
outsourcing high-risk research concepts to these small biotechs and using their services
up to and including the development of clinical candidates. In addition, prescribing
practices are changing across the healthcare sector. In the past, the physician alone was
responsible for therapy, sometimes in consultation with the pharmacist. Today, cost
pressures, negative lists, health insurance companies, hospital or drugstore purchasing organizations, the ubiquitous Internet, and even public opinion are increasingly
inuencing therapy.
This book is atextbook on drug discovery, the principles of action, and the way new
drugs are discovered and developed. It differs from the classic textbooks on medicinal
and pharmaceutical chemistry both in its structure and in its aims. It covers the basic
principles, methods, successes, and obstacles in the search for new drugs. Rather than
discussing classes of drugs in terms of their indications, it focuses on the route to the
active compound and the structural requirements for its action on aparticular target
protein or family of target proteins. As the title suggests, the book is aimed at students
and scientists in the elds of chemistry, pharmacy, biochemistry, biology, and medicine
Chemical Structures of Amino Acids, Molecular Graphics and Introduction
XV
who are interested in the art of designing new drugs using knowledge of the structural
basis of their activity at the site of action.
The rst part begins with an introduction to the history of drug research. This is
followed by adescription of serendipity as aconcept in drug discovery that is difcult
to plan but always highly valued. Selected examples from classical drug research are
presented as examples. Adiscussion of the fundamentals of drug action, the thermodynamics of ligand–receptor interactions, and the inuence of the three-dimensional
spatial structure of adrug on its efcacy round off this part.
In the second part, the search for new lead structures and their optimization and
the use of prodrug strategies are introduced. New screening technologies are discussed,
as well as the systematic modication of structures using the concept of bioisosterism
and apeptidomimetic approach.
The third part describes experimental and theoretical methods used in drug discovery. Combinatorial chemistry has provided access to alarge number of test compounds.
Gene technology can produce the target proteins in their pure form and has helped to
characterize the properties and function of these proteins from the molecular level to
the cellular assembly to the organismal level. It has bridged the gap between understanding the effects of drug therapy on the complex microstructure of a cell and the
systems biology of an organism. The spatial structure of proteins and protein–ligand
complexes is accessible through X-ray crystallography, cryo-electron microscopy, and
NMR spectroscopy. The structural principles of proteins and DNA are becoming better
understood and are increasingly providing access to the binding geometry of drugs.
Computational methods and molecular dynamics simulations, including complex conformational analysis, have also increased our understanding and modeling perspectives
of targeted drug design.
The fourth part introduces design techniques such as pharmacophore and receptor
modeling, and discusses the methods and uses of quantitative structure–activity relationships (QSAR). Insights into drug transport and distribution in biological systems
are provided, and various structure-based design techniques are presented. Adrug design case study from the author’s research concludes the rst part of this textbook.
The fth part focuses on the core question of drug design: How do drugs actually
work and how does this translate into the design of new drugs? Enzymes, receptors,
channels, transporters, and surface proteins are divided into separate chapters and discussed as agroup of target structures. The spatial architecture of the protein and the
modes of action are used to explain in detail why adrug works and why it must have
aparticular geometry and structure in order to work. These chapters illustrate the
contributions of structure-based design and medicinal chemistry optimization to the
discovery of new drugs, and highlight different aspects of the drug discovery process.
The concept of this book means that many important drugs are not covered, or are
only mentioned in passing. The same applies to receptor theory, pharmacokinetics and
metabolism, the basics of genetic engineering and statistical methods. The biochemical,
molecular biological, and pharmacological fundamentals of the mode of action of
drugs, which are important for understanding drug design, are only briey discussed.
Other disciplines, such as pharmaceutical formulation, toxicology, and clinical trials,
which are critical to the development of acompound into a medicine and its use in
patients, are not covered in this book.
The selection of examples from therapeutic areas has been made subjectively and
for didactic reasons based on case studies, and to highlight different aspects of drug
discovery. An attempt has been made to provide abalanced presentation of drug design
methods and their practical application.
The interested reader need not read the book chronologically. If the reader is interested only in drugs and their mode of action, they may start with Chap.22. The reader
who is more interested in methodology, or the medicinal chemist who wants to learn
the basics of drug design, can concentrate on Chaps.4–21.
There are many cross-references throughout the text to help the reader nd the passages needed for amore detailed understanding at aparticular point in other sections.
XVI Chemical Structures of Amino Acids, Molecular Graphics and Introduction
The following bibliography lists particularly recommended monographs and, in alphabetical order, journals and series on the subject, which are not mentioned individually
in the later chapters. The reader will also nd asummary of the most important aspects
after each chapter. Suggestions for further reading and many original articles are given
at the end of each chapter.
Literature
Monographs
L.Brunton, J. Lazo, K.Parker, Goodman & Gilman’s the pharmacological basis of
therapeutics, 11thedn, McGraw-Hill, Europe (2005)
C.R. Ganellin, S.M. Roberts (Eds.), Medicinal chemistry. The role of organic chem-
istry in drug research, 2nd edn, Academic Press, London (1993)
F.D. King (ed), Medicinal chemistry: principles and practice, 2ndedn, The Royal
Society of Chemistry, Cambridge (2003)
K.Stromgaard, P.Krogsgaard-Larsen, U.Madsen (Eds.), Textbook of Drug Design
and Discovery, 5thedn, CRC Press, Taylor & Francis Group, Boca Raton (2017)
D.Lednicer (Ed.), Chronicles of drug discovery, vol3. American Chemical Society,
Washington, DC and earlier volumes from this series (1993)
T. L. Lemke, D.A. Williams, Foye’s principles of medicinal chemistry, 6th edn.,
Williams & Wilkins, Baltimore (2008)
S.Hongmao, APractical Guide to Rational Drug Design, 1stedn, Woodhead Pub-
lishing (2015)
B.E. Blass, Basic Principles of Drug Discovery and Development, 2ndedn, Aca-
demic Press (2021)
R.Mannhold, H.Kubinyi, G.Folkers (Eds.), Methods and principles in medicinal
chemistry. Wiley-VCH, Weinheim, Series with Guest Editors
R.A. Maxwell, S.B. Eckhardt, Drug discovery. Acasebook and analysis. Humana
Press, Clifton (1990)
E.Mutschler, H.Derendorf, Drug action, basic principles and therapeutic aspects.
CRC Press: Boca Raton/Ann Arbor/London/Tokyo (1995)
R.B. Silverman, M.W. Holladay, The Organic Chemistry of Drug Design and Drug
Action, 3rdedn., Academic Press, (2014)
C.G. Wermuth, N.Koga, H.König, B.W. Metcalf (Eds.), Medicinal chemistry for
the 21stcentury. Blackwell Scientic, Oxford (1992)
Journals and Series
ACS Chemical Biology
ACS Medicinal Chemistry Letters
Annual Reports in Medicinal Chemistry
Chemistry & Biology
ChemMedChem
Drug Discovery Today
Drug News and Perspectives
European Journal of Medicinal Chemistry
Journal of Enzyme Inhibition and Medicinal Chemistry
Journal of Computer-Aided Molecular Design
Journal of Medicinal Chemistry
Methods and Principles in Medicinal Chemistry
Nature Communications
Nature Reviews Drug Discovery
Perspectives in Drug Discovery and Design
Chemical Structures of Amino Acids, Molecular Graphics and Introduction
XVII
Pharmacochemistry Library
Progress in Drug Research
Quantitative Structure–Activity Relationships
Reviews in Computational Chemistry
Science
Scientic American
Trends in Pharmacological Sciences
Nowadays the Internet, discussion platforms, and the tremendously valuable tool of
Wikipedia are available to everyone and provide access to an enormous source of information.
Chapter Abstract Videos
For each chapter, a short video provides an overview of what is covered in that chapter.
They can be accessed via the following QR codes or short URLs.
1 2 3 4
https://sn.pub/vrehez https://sn.pub/ti9pj7 https://sn.pub/vqibjb https://sn.pub/8ink1c
5 6 7 8
https://sn.pub/815bp7 https://sn.pub/keziu0 https://sn.pub/k19jip https://sn.pub/tts2en
9 10 11 12
https://sn.pub/wippd2
https://sn.pub/b19kz8 https://sn.pub/qhucur https://sn.pub/54f7da
13 14 15 16
https://sn.pub/uhz9e7 https://sn.pub/8oi55k https://sn.pub/bwhyti https://sn.pub/mkznv9
17 18 19 20
https://sn.pub/0bzx5y https://sn.pub/j7pt6b https://sn.pub/ssi0og https://sn.pub/0alfsy
21 22 23 24
https://sn.pub/ya1k72 https://sn.pub/01mfsx https://sn.pub/gqj47j https://sn.pub/wrrga8
25 26 27 28
https://sn.pub/cy407x https://sn.pub/e3r70u https://sn.pub/x4cyhg https://sn.pub/l9lvml
29 30 31 32
https://sn.pub/fc8htp https://sn.pub/ekembs https://sn.pub/ksv7om https://sn.pub/cizkno
XIX
Contents
I Foundations in Drug Research
1 Drug Research: Yesterday, Today, and Tomorrow ............................... 3
1.1 It All Began with Traditional Medicines
1.2 Animal Experiments as aStarting Point for Drug Research
1.3 The Battle Against Infectious Disease
1.4 Biological Concepts in Drug Research
1.5 In Vitro Models and Molecular Test Systems
1.6 The Successful Therapy of Psychiatric Illness
1.7 Modeling and Computer-Aided Design
1.8 The Results of Drug Research and the Drug Market
1.9 A Subject of Conict: Pharmaceuticals
1.10 Synopsis
................................................................................ 13
Bibliography and Further Reading
In the Beginning, There Was Serendipity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2
2.1 Acetanilide Instead of Naphthalene: ANew, Valuable Antipyretic
2.2 Anesthetics and Sedatives: Pure Accidental Discovery
2.3 Fruitful Synergies: Dyes and Pharmaceuticals
2.4 Fungi Kill Bacteria and Help with Syntheses
2.5 The Discovery of the Hallucinogenic Eect of LSD
2.6 The Synthetic Route Determines the Structure
2.7 Surprising Rearrangements Lead to Medicines
2.8 A Long List of Accidents
................................................................ 21
2.9 Where Would We Be Without Serendipity?
2.10 Synopsis
................................................................................ 22
Bibliography and Further Reading
................................................. 5
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Classical Drug Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3
3.1 Aspirin: ANever-Ending Story
3.2 Malaria: Success and Failure
3.3 Morphine Analogues: AMolecule Cut to Pieces
3.4 Cocaine: Drug and Valuable Lead Structure
3.5 H
3.6 Synopsis
Antagonists: Ulcer Therapy Without Surgery ........................................ 33
2
................................................................................ 36
Bibliography and Further Reading
Protein–Ligand Interactions as the Basis for Drug Action ..................... 39
4
4.1 The Lock-and-Key Principle
4.2 The Essential Role of the Membrane
4.3 The Binding Constant K
4.4 Important Types of Protein–Ligand Interactions
4.5 The Strength of Protein–Ligand Interactions
4.6 Blame It All on Water!
................................................................... 49
4.7 Thermodynamic Contributions to the Formation of Protein–Ligand Complexes
.......................................................... 24
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............................................................. 41
................................................... 42
Describes the Strength of Protein–Ligand Interactions ...... 43
i
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...... 50
4.8 What Is the Contribution of aHydrogen Bond to the Strength of Protein–Ligand
Interactions?
4.9 The Strength of Hydrophobic Protein–Ligand Interactions
4.10 Binding and Mobility: Compensation of Enthalpy and Entropy
4.11 Lessons for Drug Design
4.12 Synopsis
Bibliography and Further Reading
............................................................................ 52
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....................................................... 64
XX Contents
5 Optical Activity and Biological Eect ............................................. 67
5.1 Louis Pasteur Sorts Crystals
5.2 Structural Basis of Optical Activity
5.3 The Isolation, Synthesis, and Biosynthesis of Enantiomers
5.4 Lipases Separate Racemates
5.5 Dierences in the Activity of Enantiomers
5.6 Image and Mirror Image: Why Is It Dierent for the Receptor?
5.7 An Excursion into the World of Stereoisomers
5.8 Synopsis
................................................................................ 81
Bibliography and Further Reading
The Search for the Lead Structure
II
............................................................ 68
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6 The Classical Search for Lead Structures ......................................... 85
6.1 How It Began: Hits by In Vivo Screening
6.2 Lead Structures from Plants
............................................................ 86
6.3 Lead Structures from Animal Venoms and Other Ingredients
6.4 Lead Structures from Microbial Organisms
6.5 Dyes and Intermediates Lead to New Drugs
6.6 Mimicry: How to Copy Endogenous Ligands
6.7 Side Eects Indicate New Therapeutic Options
6.8 From the Traditional Search to the Screening of Large Compound Libraries
6.9 Synopsis
................................................................................ 93
Bibliography and Further Reading
................................................ 86
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. . . . . . . . . . . 92
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Screening Technologies for Lead Structure Discovery ......................... 95
7
7.1 Screening for Biological Activity by HTS
7.2 Color Change Demonstrates Activity
............................................... 96
................................................... 97
7.3 Getting Faster and Faster: More and More Compounds by Using Less and
Less Material
7.4 From Binding to Function: Testing in Entire Cells
7.5 Back to Whole-Animal Models: Screening on Nematodes
7.6 In Silico Screening of Virtual Compound Libraries
7.7 Biophysics Supports Screening
7.8 Screening by Using Nuclear Magnetic Resonance
7.9 Crystallographic Screening for Small Molecular Fragments
7.10 Tethered Ligands Explore Protein Surfaces
7.11 Synopsis
Bibliography and Further Reading
Optimization of Lead Structures .................................................. 115
8
8.1 Strategies for Drug Optimization
8.2 Isosteric Replacement of Atoms and Functional Groups
8.3 Systematic Variation of Aromatic Substituents: The Topliss Trees
8.4 Optimizing the Activity and Selectivity Prole
8.5 From Agonists to Antagonists
8.6 Optimizing Bioavailability and Duration of Action
8.7 Variations of the Spatial Pharmacophore
8.8 Optimizing Anity, Enthalpy, and Entropy of Binding and Binding Kinetics
8.9 Synopsis
Bibliography and Further Reading
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Contents
XXI
9 Designing Prodrugs ................................................................. 127
9.1 Foundations of Drug Metabolism
9.2 Esters Are Ideal Prodrugs
............................................................... 129
9.3 Chemically Well Wrapped: Multiple Prodrug Strategies
l-DOPA Therapy: AClever Prodrug Concept ............................................ 132
9.4
9.5 Drug Targeting, Trojan Horses, and Pro-prodrugs
9.6 Synopsis
................................................................................ 135
Bibliography and Further Reading
Peptidomimetics ..................................................................... 137
10
10.1 Therapeutic Relevance of Peptides
10.2 Designing Peptidomimetics
10.3 First Step to Variation: Modifying Side Chains
10.4 A More Courageous Step: Modifying the Main Chain
10.5 Rigidifying the Backbone by Fixing Conformations
10.6 Peptidomimetics to Interfere with Protein–Protein Interactions
10.7 Tracing Selective NK Receptor Antagonists by Ala Scan
10.8 CAVEAT: Idea Generator for the Design of Peptidomimetics
10.9 Design of Peptidomimetics: Quo Vadis?
10.10 Synopsis
................................................................................ 148
Bibliography and Further Reading
...................................................... 128
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Experimental and Theoretical Methods
III
11 Combinatorics: Chemistry with Big Numbers ................................... 153
11.1 How Nature Produces Chemical Multiplicity
11.2 Protein Biosynthesis as aTool to Build Compound Libraries
........................................... 154
........................... 155
11.3 Organic Chemistry from aDierent Angle: Random-Guided Synthesis
of Compound Mixtures
11.4 What Is Contained in Chemical Space?
11.5 Compound Libraries on Solid Support: Complete Conversion and Easy Purication
11.6 Compound Libraries on Solid Support Need Sophisticated Synthetic Strategies
Which Compound in the Solid Support Combinatorial Library Is Biologically Active?
11.7
11.8 Combinatorial Libraries with Large Diversity: AChallenge for Synthetic Chemistry
11.9 Nanomolar Ligands for G-Protein-Coupled Receptors
................................................................. 155
................................................. 156
.. 157
...... 157
... 158
... 159
................................. 160
11.10 More Potent than Captopril: AHit from aCombinatorial Library of Substituted
Pyrrolidines
11.11 Parallel or Combinatorial, in Solution or on aSolid Support?
............................................................................. 161
.......................... 161
11.12 The Protein Finds Its Own Optimal Ligand: Click Chemistry and Dynamic
Combinatorial Chemistry
11.13 Synopsis
................................................................................ 165
Bibliography and Further Reading
Gene Technology in Drug Research ............................................... 169
12
12.1 The History and Basics of Gene Technology
12.2 Gene Technology: AKey Technology in Drug Design
12.3 Genome Projects Decipher Biological Constructions
12.4 What Is Contained in the Biological Space of the Human Proteome?
12.5 Knock in, Knock out: Validation of Therapeutic Concepts
12.6 Recombinant Proteins for Molecular Test Systems
12.7 Silencing Genes by RNA Interference
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12.8 PROTAC: How to force therapeutically untargetable proteins into targeted
degradation
12.9 Proteomics and Metabolomics
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