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Preface

The last decade has seen many exciting new medicines being introduced to the
market, such as novel oral anticoagulants, novel anti-diabetics, highly effective
antiviral agents against hepatitis C, oral MS therapies, or targeted cancer therapies
to name just a few. For the first time, diseases with orphan drug designations, e.g.,
cystic fibrosis or rare blood disorders, are treated with new chemical or biological
entities. Biologics have now reached center stage especially for the treatment of
immune disorders and oncologic indications, with the anti-TNFα agent
adalimumab being the best-selling drug in 2014. These impressive successes
notwithstanding, the so-called patent cliff, a conceived lack of productivity in the
pharmaceutical industry, increasing expenses to discover and develop new thera-
peutic agents and reimbursement challenges have put pressure on the community to
only target highly innovative approaches and to focus resources in selected areas of
high expertise. With increased investments over the last years pharma companies
continue to support large R&D efforts, while new venture capital backed biotech
companies have surfaced, and universities attempt to translate their basic research
into products through collaborations and the build-up of screening centers. Apart
from this dynamic, the underlying process of drug discovery has not changed
dramatically. It still starts with a solid disease hypothesis linked to a target which
then needs precise validation (D. Sim, K. Kauser, B. Nicke) before the high-
throughput screening is started for lead identification. As pointed out by J. Eder
and P.L. Herrling, phenotypic screens have gained more attention recently, where a
cell-based assay is used to first identify leads and later – hopefully – the
corresponding target. Intractable targets, discarded as non-druggable a decade
ago, are tackled today (S. Knapp), and new chemical matter intercepting protein–
protein interactions (C. Ottmann), a revived interest in natural products (E.F. van
Herwerden, R. Süssmuth), and powerful high-throughput synthesis
(C. Rademacher, P.H. Seeberger) might help to dissect and address challenging
pathways. Meanwhile classical medicinal chemistry can rely on improved predic-
tive models (M.S. Lawless, M. Waldman, R. Fraczkiewicz, R.D. Clark) and strong
in vitro assays (G. Langer) to identify and optimize leads. Understanding their
pharmacokinetic properties (A. Reichel) is a prerequisite for lead refinement and
candidate selection, before in vivo efficacy is demonstrated in relevant animal
models (O.D. Slayden, H. Trübel, B. Albrecht, J. Hoffmann) and the potential

v
vi Preface

candidates are subjected to a thorough safety assessments (C. Stark) for final
triaging. Early identification of biomarkers to either select patients susceptible to
a certain therapy or as surrogate marker for efficacy (T. Krahn) and computational
models to simulate drug effects (J. Lippert) have become essential tools when
entering the clinical phase.
We hope the handbook conveys the excitement and progress made in drug
discovery throughout the last decade. While the process has stayed the same, it
has been enriched and reinvented along the value chain. Hence, Giuseppe di
Lampedusa’s Se vogliamo che tutto rimanga come è, bisogna che tutto cambi
[If we want things to stay as they are, things will have to change, Il Gattopardo
(1958)] might probably be an appropriate motto for this book.

Berlin, Germany Ulrich Nielsch

Ulrike Fuhrmann
Stefan Jaroch
Contents

Part I Overview
Trends in Modern Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
J€
org Eder and Paul L. Herrling

Part II Target Discovery

Functional Genomics in Pharmaceutical Drug Discovery . . . . . . . . . . . . 25
Robert Adams, Michael Steckel, and Barbara Nicke
Emerging Target Families: Intractable Targets . . . . . . . . . . . . . . . . . . . 43
Stefan Knapp
In Vivo Target Validation Using Biological Molecules in Drug
Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Derek S. Sim and Katalin Kauser

Part III Lead Generation and Optimization

High-Throughput Synthesis of Diverse Compound Collections
for Lead Discovery and Optimization . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Christoph Rademacher and Peter H. Seeberger
Sources for Leads: Natural Products and Libraries . . . . . . . . . . . . . . . . 91
Eric F. van Herwerden and Roderich D. Süssmuth
New Compound Classes: Protein–Protein Interactions . . . . . . . . . . . . . 125
Christian Ottmann
Using Cheminformatics in Drug Discovery . . . . . . . . . . . . . . . . . . . . . . 139
Michael S. Lawless, Marvin Waldman, Robert Fraczkiewicz,
and Robert D. Clark

Part IV Test systems for Efficacy and Safety

Implementation and Use of State-of-the-Art, Cell-Based
In Vitro Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Gernot Langer
vii
viii Contents

Translational In Vivo Models for Women’s Health: The Nonhuman

Primate Endometrium—A Predictive Model for Assessing Steroid
Receptor Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Ov Daniel Slayden
Predictive In Vivo Models for Oncology . . . . . . . . . . . . . . . . . . . . . . . . 203
Diana Behrens, Jana Rolff, and Jens Hoffmann
Translational In Vivo Models for Cardiovascular Diseases . . . . . . . . . . 223
Daniela Fliegner, Christoph Gerdes, J€org Meding,
and Johannes-Peter Stasch
Pharmacokinetics in Drug Discovery: An Exposure-Centred
Approach to Optimising and Predicting Drug Efficacy and Safety . . . . . 235
Andreas Reichel and Philip Lienau
Nonclinical Safety and Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Claudia Stark and Thomas Steger-Hartmann
Impact of Biomarkers on Personalized Medicine . . . . . . . . . . . . . . . . . . 285
Patricia Carrigan and Thomas Krahn
Modeling and Simulation of In Vivo Drug Effects . . . . . . . . . . . . . . . . . 313
J€
org Lippert, Rolf Burghaus, Lars Kuepfer, Bart Ploeger, Stephan Schaller,
Walter Schmitt, and Stefan Willmann

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331
Trends in Modern Drug Discovery

€rg Eder and Paul L. Herrling

Jo

Contents
1 The Beginnings of Modern Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.1 Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
1.2 Ergotamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3 Penicillin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 Steroid Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2 Where Do Chemical Lead Structures Come from Today? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.1 Origin of Libraries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2 HTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3 FBS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.4 Rational Drug Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.5 Target Family Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.6 In Silico Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.7 Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3 Where Do Targets Come from? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
4 Changing Landscape of Academic and Pharmaceutical Research . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1 Laboratory Size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.2 Research Center Size and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.3 In-House and Outsourced Research, Academic Collaborations, and Consortia . . . . . 17
4.4 Me-Too Drugs vs. Medical Breakthrough . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.5 Science Expertise and Culture at the Top . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4.6 Productivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Abstract
Drugs discovered by the pharmaceutical industry over the past 100 years have
dramatically changed the practice of medicine and impacted on many aspects of
our culture. For many years, drug discovery was a target- and mechanism-

J. Eder • P.L. Herrling (*)

Novartis Pharma AG, CH-4056 Basel, Switzerland
e-mail: paul.herrling@novartis.com

# Springer International Publishing Switzerland 2015 3

U. Nielsch et al. (eds.), New Approaches to Drug Discovery,
Handbook of Experimental Pharmacology 232, DOI 10.1007/164_2015_20
4 J. Eder and P.L. Herrling

agnostic approach that was based on ethnobotanical knowledge often fueled by

serendipity. With the advent of modern molecular biology methods and based on
knowledge of the human genome, drug discovery has now largely changed into a
hypothesis-driven target-based approach, a development which was paralleled
by significant environmental changes in the pharmaceutical industry.
Laboratories became increasingly computerized and automated, and geographi-
cally dispersed research sites are now more and more clustered into large centers
to capture technological and biological synergies. Today, academia, the regu-
latory agencies, and the pharmaceutical industry all contribute to drug discovery,
and, in order to translate the basic science into new medical treatments for unmet
medical needs, pharmaceutical companies have to have a critical mass of
excellent scientists working in many therapeutic fields, disciplines, and
technologies. The imperative for the pharmaceutical industry to discover break-
through medicines is matched by the increasing numbers of first-in-class drugs
approved in recent years and reflects the impact of modern drug discovery
approaches, technologies, and genomics.

Keywords
Pharmaceutical research
Pharmaceutical industry
R&D productivity
Target-
based drug discovery
Phenotypic screening
Lead discovery
Target discovery

1 The Beginnings of Modern Drug Discovery

Modern drug discovery is one of the most complex scientific areas and involves
many different scientific disciplines. It has its origins at the end of the nineteenth
century in the experimental biological and medical research of Claude Bernard,
Louis Pasteur, Robert Koch, Paul Ehrlich, and Joseph Lister, as well as in the great
advances in organic chemistry at the same time, and has ever since dramatically
changed the practice of medicine, our culture, and sociology. About 1,500 unique
drugs are currently known which act through more than 350 different mechanisms
(Overington et al. 2006). With these, many diseases are now curable or can at least
be controlled at the symptomatic level including bacterial, parasitic and viral
infections, rheumatoid arthritis, asthma, osteoporosis, thrombosis and other cardio-
vascular disorders, diabetes, psychiatric diseases, and various cancers. Moreover,
drugs have enabled many surgical procedures of modern medicine and even made
cell and solid organ transplantation possible.
The first 100 years of modern drug discovery were largely target and mechanism
agnostic and primarily driven by chemocentric approaches, i.e., approaches based
on a specific compound or compound class which served as starting point for further
optimization. These chemotypes were either discovered through ethnobotanical
knowledge or derived from natural ligands and substances. Serendipity, however,
was also an important success factor in many instances. In the following we list a
few examples to illustrate how drugs were discovered during this time period.
Trends in Modern Drug Discovery 5

1.1 Aspirin

Extracts of the bark from the willow tree were used for thousands of years in Europe
and North America for pain relief, treatment of inflammation, and fever. The active
ingredient of the bark extract was first isolated by the German chemist Johann
Andreas Buchner in 1828 and named salicin after the Latin name for the white
willow (Salix alba). The glycoside can be converted to salicylic acid by hydrolysis
and subsequent oxidation (Fig. 1). Felix Hoffman, a chemist at Bayer in Germany,

Fig. 1 Drugs discovered during the first 100 years of modern drug discovery were mainly based
on ethnobotanical knowledge or derived from natural ligands and substances
6 J. Eder and P.L. Herrling

systematically searched for derivatives of salicylic acid in 1897. His search was
triggered by his father who suffered from rheumatoid arthritis and did not tolerate
high doses of salicylic acid due to intestinal tract irritation and emesis. One of the
first derivatives he synthesized was acetylsalicylic acid which is known since 1899
as Aspirin® (Schr€or 2008). It took more than 75 years until it was discovered that
the chemical derivatization also led to an advantageous change in the mechanism of
action as it turns the drug into an irreversible inhibitor thereby preserving its
therapeutic effect beyond compound exposure. The latter is the basis for the success
of low-dose acetylsalicylic acid treatment as anticoagulant therapy used by millions
of patients today.

1.2 Ergotamine

The fungus Claviceps purpurea and other clavicipitaleans form ergot sclerotia to
produce their spores in oat, rye, wheat, and other grasses. These sclerotia contain
more than 50 different indole alkaloids, referred to as ergot alkaloids. Many of these
are highly toxic due to their vasoconstrictive properties leading to gangrenous loss
of the limbs, hallucinations, and dementia. The first documented ergotism epidemic
of human toxicity occurred in central Europe in 857 AD, and it took almost 1,000
years to realize the causal relationship and improve agricultural practices. In herbal
medicine ergot was first mentioned in the late sixteenth century for use in obstetrics
to induce uterine contractions and hasten childbirth, to reduce postpartum hemor-
rhage, and to induce abortion. When migraine was proposed to be caused by
vasodilation by sympathetic deficit in the mid-nineteenth century, the British
surgeon Edward Woakes recommended ergot as a vasoconstricting treatment in
1868 (Woakes 1868). The Swiss biochemist Arthur Stoll isolated ergotamine as the
active ingredient of ergot sclerotia in 1918 at Sandoz, and the company started to
market ergotamine (Gynergen®) in 1921 for the treatment of migraine. Twenty
years later, Albert Hofmann, a chemist and coworker of Arthur Stoll who worked
on the isolation and synthesis of active ergot constituents, wanted to engraft the
respiratory and circulatory stimulating effect of nicotinic acid diethylamide
(marketed under the trade name of Coramine®) onto the ergotamine structure.
The result was the discovery of lysergic acid diethylamide, better known as LSD,
a psychedelic drug (Fig. 1).

1.3 Penicillin

Alexander Fleming serendipitously discovered the antibiotic effect of the fungus

Penicillium rubens in 1928 when working with staphylococci cultures (Fleming
1929). One such culture was contaminated with a fungus, and the colonies of
staphylococci around the mold were destroyed, whereas other colonies farther
away were unaffected. He grew the fungus in pure culture, established that it also
killed other disease-causing bacteria, and named the unknown active ingredient
Trends in Modern Drug Discovery 7

penicillin. Only 12 years later the pure substance was isolated and characterized and
its chemical structure determined (Fig. 1). The success of penicillin and its
derivatives triggered a search for additional antibiotics produced by other fungi
and led, for example, to the discovery of cephalosporins (Fig. 1) which have the
same mechanism of action but are less prone to hydrolysis by bacterial
β-lactamases.

1.4 Steroid Hormones

The first steroid hormone was isolated from the urine of pregnant women by Adolf
Butenandt in 1929 (estrone; see Fig. 1) (Butenandt 1931). To guide the isolation, he
used a specific test system to detect the activity of the hormone. In the following
years, he and others isolated and structurally characterized other female (estradiol,
estriol) and male (testosterone, androsterone) sex hormones, progestogens (proges-
terone), and corticosteroids (e.g., cortisol). Their chemical optimization toward oral
bioavailability and the search for more potent analogs led to a number of important
drugs in the field of cancer (antiestrogens, antiandrogens; see Fig. 1) and immune
diseases (e.g., dexamethasone). In addition, the idea to combine an estrogen and
progestogen by Carl Djerassi and Gregory Pincus in the 1950s gave rise to the first
oral contraceptive pill and revolutionized family planning in the industrialized
world.
Until modern molecular biology techniques were established in the mid-1980s,
the molecular basis of the pharmacology of most drugs was not known. Pharmaco-
logical receptors, a concept proposed by Langley (1905), were only a model
inferred from dose-response curves derived from measuring the effect of pharma-
cological agents applied to whole animals or isolated tissues, such as the muscle,
gut, and heart in organ bath apparatuses (Fig. 2). This was still the case in 1975
(Goodman and Gilman 1975). It was assumed already in 1880 by Langley (1880)

Fig. 2 Organ bath used in the

author’s laboratory (PH) in
the 1980s
8 J. Eder and P.L. Herrling

that actions of pharmaceutical drugs are governed by the law of mass action. This
concept was further elaborated by Clark (1920). The receptor existed only as an
abstract model, but its interactions with pharmacological drugs could be measured
by constructing logarithmic dose-response curves as well as the interactions of
agonists and antagonists at a particular receptor (Kenakin 1987; Arunlakshna and
Schild 1959). The availability of radioactive selective receptor ligands and the
development of receptor binding studies by Robert Lefkowitz et al. (1970) have
greatly helped to localize receptors in different organs and tissues in particular in
the brain (Cortes et al. 1987) as one example of many.
Meanwhile, due to advances in molecular biology, genetics, protein sequencing,
and computing, many receptors and other drug targets are cloned, purified, and
described atom by atom in spatial models allowing true target-based drug discov-
ery, i.e., studying the interactions of targets with drug molecules in isolation and
visualizing and calculating their interactions at atomic scale (Falchi et al. 2014;
Chen et al. 2012).

2 Where Do Chemical Lead Structures Come from Today?

Target-based drug discovery has enabled a great expansion of chemotypes and

pharmacophores available for the medicinal chemist during the past three decades.
New techniques like high-throughput screening (HTS), fragment-based screening
(FBS), crystallography in combination with molecular modeling, and combinatorial
and parallel chemistry have created a considerable diversity of chemical lead
structures well beyond the known natural products and ligands used as chemical
starting points for drug discovery in the past. Moreover, this wealth of chemotypes
can now be used as a source for tool compounds to study unexplored biological
space and find new drug targets or for phenotypic screening using systems-based
approaches to identify drug candidates in a target-agnostic manner (see below).
Figure 3 shows examples of successful target-based drug discovery projects using
the different methods available for identification of lead structures. These include
high-throughput screening of diverse chemical libraries, fragment-based screening,
rational drug design, the use of target family knowledge, and in silico drug
discovery methods.

2.1 Origin of Libraries

Typically, the libraries are composed of the compounds synthesized over time by
individual companies and influenced by a company’s history, e.g., Novartis has a
large number of ergot compounds in its library, and Roche would have many
benzodiazepines. But as many companies work on similar targets or scaffolds,
there must also be some overlap between the libraries. Nevertheless these libraries
are a key component of the success of pharmaceutical companies, although they
have once been in danger of getting lost. At the time combinatorial chemistry
Trends in Modern Drug Discovery 9

HTS

Oxazolidinone Rivaroxaban

FBS

7-Azaindole Vemurafenib

Raonal design

Pepstan Tetrapepde transion

state mimec

Aliskiren

Target family knowledge

2-aminopyrimidine (PKC) Imanib (BCR_ABL)

In silico

Anilinoqionazoline Gefinib

Fig. 3 Target-based drug discovery has enabled a great expansion of pharmacophores by using a
variety of different methods

became possible in the 1980s eventually allowing the rapid synthesis of millions of
compounds it was thought that all possible compounds could be made when needed
by starting from individual scaffolds, and the historical libraries were neglected for
10 J. Eder and P.L. Herrling

a while. However, it became apparent in HTS that the hit rate, when using these
combinatorial libraries, was distinctly lower than with the historical libraries
(Lahana 1999). One reason for this was that combinatorial libraries were strongly
dependent on chemical parameters, such as the possibility to do chemistry with
molecules attached on beads rather than on potential biological activity alone. This
insight led to a revalorization of the collection of historical compounds that had
been made for pharmacological activity. It also led some companies to maintain and
expand their natural-compound libraries as these can be seen as compounds
selected for biological activity for hundreds of millions of years. Medically useful
compounds from natural substances are described above. Today the realization that
even the millions of compounds available cover only a small part of the biologically
active compound universe makes it important to continue the efforts to diversify our
libraries as repeatedly few or no ligands are found in the existing libraries for some
newly discovered targets.

2.2 HTS

Compound collections used for high-throughput screening are typically based on

chemically diverse molecules as well as on chemotypes from previous projects and
can reach a size of 1–2 million substances. The compounds are screened in
biological test systems, and hits, once validated by independent biochemical or
biophysical methods, are further optimized to drug candidates. An example is the
discovery of the anticoagulant rivaroxaban, a factor Xa inhibitor approved by the
FDA in 2011. The HTS hit selected for further optimization was an oxazolidinone
derivative (Perzborn et al. 2011), a compound class previously worked on for
inhibition of the 50S ribosomal subunit A site in bacteria.

2.3 FBS

A specific variant of HTS is fragment-based screening. It is based on the idea that

smaller molecules (usually with molecular weights below 250 Da) are better suited
to sample the chemical space because it is much less complex for small molecules
than it is for bigger ones. Hits are generally more frequent but may only bind
weakly to the biological target, which requires growing them or combining them to
produce a lead with a high affinity. So far the only successful example of this
relatively new technology is the BRAF V600E mutant kinase inhibitor
vemurafenib. The underlying chemotype was discovered by FBS using a panel of
recombinant kinases (Tsai et al. 2008). The 7-azaindole compound was subse-
quently optimized to the final inhibitor by conventional medicinal chemistry
methods.
Trends in Modern Drug Discovery 11

2.4 Rational Drug Design

The renin inhibitor aliskiren has been approved for treatment of hypertension in
2007. Renin is an aspartic protease which catalyzes the rate-limiting step in the
renin-angiotensin system. Aliskiren is the product of rational drug design utilizing
the inhibitory principle of pepstatin, a naturally occurring hexa-peptide which
contains the unusual γ-amino acid statin. The statin-based inhibitory principle
was grafted onto small peptide-like compounds derived from the natural renin
substrate, and these compounds were further optimized to the final drug using
structural information (Maibaum and Feldman 2009).

2.5 Target Family Knowledge

Leveraging target family knowledge is another way of generating chemical starting

points for targets which are members of larger protein families such as kinases,
proteases, E3 ligases, or G-protein-coupled receptors. The BCR-ABL kinase inhib-
itor imatinib, which revolutionized the treatment of chronic myelogenous leukemia
(CML), was discovered based on an aminopyrimidine lead compound that was
originally identified in a screen for inhibitors of protein kinase C (Capdeville
et al. 2002). Chemical optimization toward BCR-ABL selectivity and oral bioavail-
ability led to the final molecule.

2.6 In Silico Methods

The availability of three-dimensional structures and ever more sophisticated com-

puter modeling programs also enables the in silico discovery of chemical starting
points. An example is gefitinib, an epidermal growth factor receptor tyrosine kinase
inhibitor for the treatment of lung and breast cancers. The proposed catalytic
mechanism was used to define a query for structure-based searches which led to
the discovery of anilinoquinazolines as potent inhibitors and suitable lead structure
for this enzyme (Ward et al. 1994).
Today, in many cases, the X-ray crystal structure of a target is available early
during a drug discovery project, and even the structures of membrane receptors can
now be solved. With this structural information, it is often possible to combine the
different lead-finding approaches into a broader, integrated lead-finding strategy.
The structural information gained from each individual hit thereby adds to an
overall understanding of how best to fill the binding pocket of a target and can be
used to design new chemotypes based on a holistic understanding of the
contributions of many diverse molecular substructures. Different to previous
times, individual compound classes thereby no longer serve as separate and uncon-
nected starting points for the medicinal chemist but contribute to an integrated
strategy. Moreover, hit finding, in particular FBS, can be used to exhaustively map
a target’s binding site and provide the chemists and molecular modelers with