Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177 S.-Y. Han and S.-H.

Kim 169

Review Article
Introduction to Chemical Proteomics for Drug Discovery and
Development

Sung-Young Han1, 2, Seong Hwan Kim2

1
Department of Chemistry, University of Texas at Dallas, Richardson, TX, USA
2
Laboratory of Chemical Genomics, Bio-Organic Science Team, Drug Discovery Research Hub, Korea
Research Institute of Chemical Technology, Daejeon, Korea

A fundamental goal of chemical proteomics is to identify target proteins for bioactive small
molecules and then apply them to drug discovery and development as valid and drugable tar-
gets. Here, we introduce integrated technologies for the rapid identification of target proteins,
methodologies for validating them as drugable targets, and applications of chemical proteomics
in drug discovery and development.

Keywords: Photoreactivity / Rational drug design / Structure elucidation /

Received: September 19, 2006; accepted: February 1, 2007

DOI 10.1002/ardp.200600153

Introduction

Chemical proteomics is a currently emerging field with a

mission to identify and validate a target protein that
directly binds with a binder such as a bioactive small
molecule in a rapid, systematic, and comprehensive man-
ner by design, synthesis, and application of relevant che-
mical probes. As a multidisciplinary science, chemical
proteomics proposes the integration of tools and technol-
ogies from a variety of disciplines, chemistry, biochemis-
try, biology, structural biology, proteomics, and infor-
matics (Fig. 1). Thus, an integrated strategy in chemical
proteomics can provide the information about the bind-
ing site of bioactive small molecule in its target protein
and, importantly, it could be the starting point to
develop the drug screening systems based on the struc-
ture of target protein.
Mostly, the discovery of signal transduction pathway
contributing to the disease state has been done in the
first step of the processes for developing new drugs. The Figure 1. Chemical proteomics as a multidisciplinary science.
understanding of signaling pathways and further map-
ping of the key signaling molecules in biochemical path- ways have provided how cells, organs, and the body are
aberrantly controlled in disease state, and this had an
Correspondence: Seong Hwan Kim, Ph.D., Laboratory of Chemical
enormous impact on the development of new therapeu-
Genomics, Bio-Organic Science Team, Drug Discovery Research Hub, tic approaches for the treatment of nearly every human
Korea Research Institute of Chemical Technology, P. O. Box 107, Yu- disease [1]. Thus, the efforts to reveal the signaling path-
seong-gu, Daejeon 305-600, Korea
E-mail: hwan@krict.re.kr ways and molecules that are deeply involved in certain
Fax: +82 42 861-0307 disease states have continuously developed the mechan-

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170 S.-Y. Han and S.-H. Kim
ism-based drug discovery, but it is not enough to develop
new drugs for treating patients since the communication
among the disease-related signaling pathways is too
sophisticated to easily decipher the pathophysiological
network of the disease-specific signals.
Actually, as well as the understanding of the cross-reac-
tion between a bioactive small molecule and its target
protein(s) that can elucidate the biological actions of
both, the structural information about candidate target
may prove useful in ultimately predicting the interaction
of a bioactive small molecule with its non-targeted pro-
tein(s), which can lead to multiple side effects. Therefore,
the structure-based drug design approach based on the
,
understanding of what disease-related targets are’ in the
outset of the drug development process could cover the
shortage of mechanism-based drug discovery including
unpredicted side effects.
As a rapid growth of structural biology for determining
the protein structure and an advance in mass spectrome-
try (MS) analysis, a structure-based drug design approach
is considered a central component in the process of drug
discovery and development. In fact, advances in process
automation and informatics have aided the development
of high-throughput X-ray crystallography and the use of
this technique for structure-based lead discovery [2, 3].
Thus, virtual screening coupled with high-throughput X-
ray crystallography is now focused on identifying one or
more binding small molecule fragments from chemical
libraries consisting of hundreds of small molecule frag-
ments. The information about target proteins/peptides
can also make several other applications feasible. Two MS-
based strategies, function-based and affinity-based, have
been employed in recent years for screening and evalua-
tion of compounds [4]. In the function-based approach,
the effects of compounds on the biological activity of a tar-
get molecule are measured, and in the affinity-based
approach, compounds are screened based on their bind-
ing affinities to target molecules. Therefore, the elucida-
tion of interaction between a binder (e. g. substrate for
enzyme, ligand for receptor, or bioactive small molecule)
and its target protein(s) could be a promising way to speed
up and further industrialize target-based drug discovery
[5]. On the other hand, the efforts in chemical proteomics
would help to prioritize candidate targets, streamline the
drug development pipeline, and hopefully reduce the
number of failures downstream.
With the fact, that chemical proteomics approaches
have gained more interests in the early stage of drug dis-
covery and development together with chemical geno-
mics that is to find and optimize chemical compounds
for its use to directly test the therapeutic relevance of
new targets revealed through genome sequencing [6], in
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
this review, the importance of chemical proteomics and
several tools used in this field will be introduced and,
finally, its application in the process of drug discovery
and development will be discussed briefly.
Impact of chemical proteomics
High-throughput screening assays used routinely is for
identifying a bioactive small molecule that can bind its
target candidates and modulate their activities or func-
tions, but a very large proportion of the hits identified
are false positives that do not bind to the target binding
site. This limitation can be overcome with the use of vali-
dated target proteins that are identified and evaluated by
chemical proteomics approaches.
Chemical proteomics study on the target proteins of
bioactive small molecules can also reveal alternative cel-
lular modes of small molecule action, which was an
unrecognized therapeutic potential previously. For
example, pyrido[2,3-d]pyrimidines, which were initially
developed as anti-proliferative agents targeting protein
tyrosine kinases involved in cancer [7], were found to
lack selectivity for tyrosine kinases. Instead, these inhibi-
tors were established as potent inhibitors of several ser-
ine/threonine kinases such as p38a and RIPK2. The identi-
fication of alternative target proteins for bioactive small
molecules can provide new insights into their cellular
modes of action. This could be highly associated with the
following; the identification of target proteins for an
approved medication by using chemical proteomics
approaches play a pivotal role in the process of finding
new uses outside the scope of the original medical indica-
tion for existing drugs that is known as redirecting,
repurposing, repositioning, and reprofiling [8]. Reposi-
tioning success stories and companies leveraging reposi-
tioning strategies are increasing in number, but it should
not be discussed here.
To summarize, the elucidation of the specific interac-
tion between bioactive small molecules and their part-
ners, target proteins by using integrated chemical proteo-
mics strategies contributes to our understanding of how
bioactive small molecules work in cells and the body, and
consequently to the development of medicines.
Target proteins and binding sites
The biological function of most proteins depends on
direct and specific binding of their binders to particular
spatial areas, the binding sites. Since the interaction of
binders with target proteins affects their functional
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
activities by changing the protein conformation, trigger-
ing (or blocking) the protein post-translational modifica-
tion such as phosphorylation or competing with sub-
strates, the understanding of thermodynamics (or ener-
getic stability) of interaction is important to elucidate
the biological activities of small molecules in cells.
Binding site (or pocket) can be defined as the region of
a protein that associates with a binder and it usually con-
sists of a cavity in the protein surface formed by a particu-
lar arrangement of amino acids. Binding depends on for-
mation of contacts between chemical groups of a binder
and those in the binding site of the target protein. In par-
ticular, the cavity in the structure of a protein deter-
mines the recognition features of the target protein.
Thus, the characteristics of a binding site can provide the
missing link needed for a thorough understanding of the
correlation between chemistry space and genome space.
Recently, advanced and integrated methods for charac-
terizing functional binding sites from a three-dimen-
sional (3D) perspective have been developed and widely
used; the variety of methods using computer algorithms
have been continuously developed and can be commer-
cially purchased from several companies such as Accelrys
Software, Inc. (http://www.accelrys.com) and Tripos, Inc.
(http://www.tripos.com). Using these methods, the virtual
binding sites of proteins can be identified or a suffi-
ciently reliable homology model can be built [9], but the
main limitation such as a high number of false positives
can not be excluded. This is the major bottleneck of in
silico approaches.
In order to upgrade the quality of the protein models,
the effort to improve the experimental methods such as
X-ray crystallography and nuclear magnetic resonance
(NMR) has been continuously made. The recent advances
in the automation of protein crystallization and in X-ray
data collection/analysis have lead to the rapidly growing
number of protein structures collected in the Protein
Data Bank (PDB; http://www.pdb.org) [10]. Parallel with
this effort, the experimental identification and valida-
tion of target proteins and/or binding sites by using inte-
grated strategies in chemical proteomics should be also
performed since the precise elucidation of interaction
between binders and their target candidates can help us
to determine the crystal structure of proteins.
Technologies for purifying/enriching target
proteins/peptides
For elucidating the physical mode of action for bioactive
small molecules identified by using cell-based, mechan-
ism-based or effect-based screening system, it should be
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Chemical Proteomics in Drug Discovery 171
considered first, how its binding partners can be purified
from the complex proteome. Several approaches such as
the use of nanoparticle, photoaffinity probe, activity-
based probe (ABP), and chemical affinity matrix have
been developed to purify/enrich and identify target pro-
teins/peptides that can directly interact with a bioactive
small molecule [11 – 13].
Nanoparticles
Several forms of nanoparticles have been used in biologi-
cal separation. In particular, biomolecule-conjugated
gold nanoparticles (AuNPs) are the most popular probes
because of their advantages such as the readily assem-
bling with thiolated molecules, the large area/volume
ratio for investigating 3D interactions, and the ease of
separation by centrifugation [14, 15]. Recently, a new
approach of using carbohydrate-encapsulated AuNP has
been introduced [11]. This allows rapid mapping of carbo-
hydrate-recognition peptide sequences in the target pro-
teins.
Surface-modified magnetic nanoparticles can act as a
general agent to separate, transport, and anchor a pro-
tein with several advantages such as their high surface/
volume ratio, good solubility, faster movement/easy
entry into cells, and magnetically controllable aggrega-
tion behavior that allow the intensive steps of centrifuga-
tion omitted [16].
Photoaffinity probe
Much attention has been devoted to the application of
photoaffinity labeling to the study of small molecule-tar-
get protein interactions since photoaffinity techniques
are especially useful to elucidate the protein structure at
the interface of bioactive small molecules by photoche-
mically labeling interacting sites [17 – 19].
Conceptually, the structure of photoaffinity probes
consists of four distinct functional elements; (a) a bioac-
tive small molecule, (b) tags (such as biotin) for identify-
ing and/or purifying the probe-target protein complex,
(c) a linker region, and (d) a photoreactive moiety capable
of covalently binding to target proteins (Fig. 2). Impor-
tantly, the design of chemical probes runs parallel to
structure – activity relationships (SAR) study because
probes should retain the biological activity as its parent
compound does [20, 21]. Generally, the introduction of a
photoreactive moiety and a biotin into the structure of a
bioactive small molecule causes the decrease of biologi-
cal activity, but probes with as much as 1000-times lower
activity can still be useful for investigating binder-pro-
tein interactions [17].
Biotin is a powerful tag for purifying the probe-target
protein/peptide complex based on the biotin-avidin inter-
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172 S.-Y. Han and S.-H. Kim
Figure 2. Structure of a biotin-tagged photoaffinity probe. A bio-
tin-tagged photoaffinity probe consists of four distinct functional
elements, a bioactive small molecule, biotin, a linker region (e. g.
PEG or alkyl), and a photoreactive moiety (e. g. azide, diazirine,
or benzophenone).
action that is the strongest non-covalent interaction
(Kd = 10 – 15 M) [17, 18]. Biotin-tagged photoaffinity probes
can be useful not only for the separation of the probe-tar-
get protein / peptide complex in mixture (Fig. 3), but also
for the indirect visualization of this complex by using
the chemiluminescent reaction of horse-radish peroxi-
dase conjugated avidin [22, 23].
The linker region between biotin, photoreactive moi-
ety, and the bioactive small molecule can serve multiple
purposes; (a) to provide enough space to prevent steric
hindrance that could decrease interactions between bin-
der and active site of target protein in living cells, (b) to
probe the structural requirements for optimal biological
activity. In order to modulate the membrane permeabil-
ity of a chemical probe in living cells and tissues, the
alkyl linker spacer can be used. Polyethylene glycol (PEG)
can also increase the bioavailability of probes by improv-
ing its solubility in aqueous solutions.
Photoreactive moieties such as an azide, a diazirine,
and a benzophenone group, have been used as precursors
for the highly reactive intermediates, which are gener-
ated upon photolysis [17 – 19]. Perfluorophenyl azide is
the most widely used photolabeling reagent since it can
be prepared easily. It belongs to a new class of photolabel-
ing reagents with improved C-H insertion efficiency com-
pared with nonfluorinated analogues. The fluorine sub-
stitution on the ortho-position of an azide group can elim-
inate the unfavorable ketenimine formation, which is
less reactive with target proteins, and sufficiently extend
the lifetime of the highly reactive singlet nitrene, which
is important to obtain a stable covalent linkage. Trifluor-
omethylaryldiazirine has been used as the photoreactive
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
Figure 3. Identification of target protein(s) by using biotin-tagged
photoaffinity probes. The UV-cross-linked complex of a biotin-
tagged photoaffinity probe with target protein(s) can be purified
and identified by using an avidin column and MS analysis,
respectively.
group due to its many useful features; (a) good chemical
stability in various reaction conditions that may facili-
tate the use of diazirines as carbene precursors; (b) photo-
activatability under long-wavelength UV light (wave-
length 350 – 360 nm) that minimize damage to pro-
teins;(c) generation of highly reactive carbene that vir-
tually reacts with proteins with no intramolecular rear-
rangements. Benzophenone has been also used for photo-
affinity-labeling experiments because of its photoactivat-
ability at long wavelength (e. g. 365 nm). Benzophenone
reacts preferentially with C-H bonds within 3.1
of the
carbonyl oxygen and its high lipophilicity can be feasible
to modulate the hydrophobicity and cell permeability of
probes.
Activity-based probe (ABP)
,
The field activity-based proteomics’ makes use of ABP for
profiling the functional state of enzymes in complex pro-
teome [24 – 27]. ABP generally consists of three basic ele-
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
Figure 4. Two basic designs of ABP-based on the target selec-
tivity. In the direct ABP approach, well-characterized affinity
labels can be incorporated as the reactive group (RG) to direct
probe reactivity toward enzymes sharing a similar catalytic
mechanism and/or substrate specificity, but in the non-direct
ABP approach, libraries of candidate probes are synthesized
with variable binding groups appended to a common RG.
ments (Fig. 4); (a) an electrophilic reactive group (RG) that
is able to covalently attach to the active site of an
enzyme, (b) a tag (e. g. biotin or fluorophore) that is useful
for subsequent purification or visualization of probe-
labeled enzymes, (c) a linker that connects these two ele-
ments, provides selective binding interactions, and pre-
vents steric congestion [28].
Based on a range of chemical scaffolds, ABPs have been
developed for more than a dozen enzyme classes includ-
ing proteases, kinases, phosphatases, glycosidases, and
oxidoreductases. The selectivity of a chemically reactive
group in ABP allows specific proteins or protein subsets
to be tagged and purified or visualized (Fig. 5). As a result,
the application of ABP is able to identify novel enzymatic
proteins and characterize the mode of action of bioactive
small molecule. The design and biological application of
ABP has been reviewed in detail by Evans and Cravatt
[29].
Two general strategies have been introduced for the
design of ABP as shown in Fig. 4 [25, 26]. In the direct ABP
approach, well-characterized affinity labels can be incor-
porated as the RG to direct probe reactivity toward
enzymes sharing a similar catalytic mechanism and/or
substrate specificity. This can be feasible to identify novel
members of enzyme family to react with well-character-
ized RG [30]. Whereas, in a second strategy referred to
non-direct ABP, libraries of candidate probes (biotiny-
lated sulfonate ester in Fig. 4) are synthesized with vari-
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Chemical Proteomics in Drug Discovery 173
Figure 5. Activity-based proteomics by using ABP. A typical
ABP consisting of an electrophilic reactive group (RG, arrow)
and a tag (fluorophore; circle) can be labeled with its target
enzyme(s) in a complex proteome and the activity-dependent
labeling event can be visualized by using in-gel fluorescence
scanning.
able binding groups appended to a common RG, and
these reagents are screened against complex proteome to
identify activity-based labeling events. This method can
facilitate the identification of compounds possessing
both selective proteome reactivities and novel bioactiv-
ities [31].
Chemical affinity matrix
In order to identify target protein(s) for a bioactive small
molecule by using chemical affinity matrix, suitable
attachment sites for immobilization should be predicted
in a small molecule from SAR data obtained with collec-
tions of structurally related compounds. However, in the
absence of any of such data, several potential attachment
sites can be selected to ensure that at least one of them
enables the immobilization of a bioactive small molecule
without conferring steric hindrance with respect to target
binding through a systematic trial-and-error approach.
Small molecules possessing a functional group such as
a solvent-exposed amino, carboxyl, or hydroxyl moiety
can be covalently coupled to a suitable chromatography
resin; a variety of chromatography resins are commer-
cially available that permit the immobilization of bioac-
tive small molecules to the terminal functional groups of
hydrophilic spacer molecules. After verifying retention
of the biological activity, the small molecule-conjugated
chemical affinity resin can be utilized for the preparative
purification of target proteins from the relevant biologi-
cal extracts [32 – 34].
Importantly, two kinds of chemical affinity matrices
(positive and negative affinity matrices) should be run
simultaneously; despite of structural modification, posi-
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174 S.-Y. Han and S.-H. Kim
Figure 6. Identification of target protein(s) by using chemical
affinity matrix. Target proteins can be captured by chemical affi-
nity matrices and, after the following processes of washing, elu-
tion and trypsin digestion, the comparative profiling of bound
peptides allows rapid sequence mapping of positive chemical
probe-binding peptides (arrow-indicated) by LC-MS/MS.
tive affinity matrix retains the significant activity and
specificity, but negative affinity matrix does not exhibit
any potent activity [13]. This approach can differentiate
positive affinity matrix-specific binding proteins/pep-
tides from those bound nonspecifically to both matrices
(Fig. 6). Using affinity matrices, several proteins such as
FK506-binding protein and mammalian histone deacety-
lase 1 have been identified [35, 36].
Integration of liquid chromatography (LC) and
MS analysis
The combination of LC and MS has had a significant
impact on drug development over the past decade. Con-
tinual improvements in LC/MS interface technologies
combined with powerful features for structure analysis
have resulted in a widened scope of application.
In general, the proteins that are enriched by using che-
mical tools such as probes or affinity matrices can be
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
separated by gel (e. g. SDS-PAGE) and subsequently ana-
lyzed by MS instruments. However, due to the exclusion
limitation in the sample preparation step and the lim-
ited sensitivity of commonly used protein staining
reagents, the traditional separation method (e. g. two-
dimensional gel electrophoresis) can not offer a lot of
information in the lower molecular weight fraction and
the low-abundance proteins of biological samples. To
overcome this problem, the enriched target proteins can
be digested with trypsin, and the resulting mixture is
then subjected to nanoflow reverse phase LC-MS/MS anal-
ysis. Liquid-based separation can easily reach into the
lower molecular weight protein and peptide range, an
area that is largely inaccessible to standard gel-based pro-
teomics. Therefore, advanced and integrated technolo-
gies such as electrospray ionization-MS/MS-integrated
nanoflow reverse phase HPLC for the separation/identifi-
cation of peptide mixtures are now being increasingly
used in the field of chemical proteomics [34, 37]. As
shown in Fig. 6, target proteins can be captured by che-
mical affinity matrices and after the following processes
of washing, elution, and trypsin digestion, the compara-
tive profiling of bound peptides allows rapid mapping of
positive chemical probe-binding peptide sequences by
nanoflow LC-MS/MS.
Consequently, the successful implementation of che-
mical proteomics critically depends on not only the effi-
ciency of affinity purification procedures, but also the
sensitivity of MS analysis. For reference, the basic of MS,
MS-based proteomics, and its applications (including tar-
get identification and characterization, structure eluci-
dation of synthetic compounds, and early drug metabo-
lism and pharmacokinetics) in early stage of target-based
drug discovery have been well-reviewed in the literatures
[4, 38, 39].
Target validation by surface plasmon
resonance (SPR) technology
To verify the specificity of the observed target proteins,
simple experiments such as western blot analysis and
competition binding assay were traditionally used
[12, 23, 40]. However, these technologies do not provide
quantitative results of the relative sensitivities for the
bioactive small molecule to the target protein and these
are not enough to turn out the initially identified pro-
teins (or candidates for target proteins) to be a valid tar-
get. Therefore, a need for target assessment that can
prioritize a target candidate from an increasing number
of feasible targets being discovered through several tech-
nologies is required.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
Figure 7. SPR sensorgram presenting SPR response (or reso-
nance signal) plotted against time. The sensorgram displays the
association and dissociation of complexes over the entire course
of an interaction with the kinetics.
Physicochemical properties for molecules binding to
its target protein affect the biological function of target
protein. Thus, the data showing the kinetics between
small molecules and proteins could be particularly help-
ful in target assessment.
Without any labeling, SPR imaging permits monitor-
ing of biomolecular interactions by detecting the inten-
sity change of reflected lights resulting from changes in
the refractive index on the gold surface [41, 42]; the
change in mass concentration at the surface can be
detected in real time with data presented as a sensor-
gram (SPR response plotted against time), which displays
the association and dissociation of complexes with the
kinetics (Fig. 7). However, before examining the kinetics,
the purified or recombinant target proteins should be
prepared and then immobilized onto the sensor surface
as an interaction partner. Immobilization occurs by
direct coupling to the surface or via a capture molecule
coupled to the surface.
Recent SPR instruments have improved sensitivity and
sample capacity, and better tools for sample recovery and
the interface with MS. Therefore, the kinetics between
small molecules and target proteins can be simulta-
neously analyzed and/or those with high affinity and spe-
cificity to the target can be directly identified in the fol-
lowing MS analysis.
Applications of chemical proteomics
Methods for chemical probes can provide a new avenue
not only for identifying novel target proteins (target dis-
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Chemical Proteomics in Drug Discovery 175
Figure 8. Chemical proteomics and its applications in drug dis-
covery and development.
covery), but also for identifying/evaluating chemical inhi-
bitors thereof (inhibitor discovery) as shown in Fig. 8 [26].
The identification and functional annotation of the
relevant binding site(s) in a target protein for a bioactive
small molecule can provide new strategies in the process
of drug discovery and development such as structure-
based drug design and lead optimization [24]. Using
direct binding SPR assays, compounds can be rapidly
identified to be with specificity in the binding site of a
validated target protein or candidates. For example, the
kinetic data obtained from SPR biosensors has been used
in the screening of kinase inhibitors or potential prion
disease therapeutics [43, 44]. After compounds screened,
the approach to find and optimize the lead compounds
can be followed [45]. A new strategy for improved second-
ary screening and lead optimization using high-resolu-
tion SPR characterization of compound-target interac-
tions has been recently reviewed [46]. In this report, the
structure-based biophysical analysis method integrating
SPR with bioinformatic approaches and mutation studies
in the early drug discovery process suggested to be used
as a cost-effective alternative to high-throughput screen-
ing methods in cases when detailed binding site informa-
tion is available. Binding site-modified proteins can be
used as reference targets in direct binding SPR assays
aimed at identifying compounds with specificity to bind-
ing site of real target protein.
In addition, ABP per se has recently been shown to have
a great potential to facilitate the process of lead drug
identification [24]; for example, of hypothetical lead
drug candidates, the lead drug can show the most specifi-
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176 S.-Y. Han and S.-H. Kim
city for the intended drug target in a competition bind-
ing assay with the chemical probe.
Together with secondary screening and lead optimiza-
tion, SPR technology can also be applied in a variety of
fields including activity characterization, compound spe-
cificity studies, early in vitro ADMET (adsorption, distribu-
tion, metabolism, excretion, and toxicity) evaluation and
quantitative SAR analysis [45]. In clinical analyses such as
immunogenic study and food industry, the presence of
pathogens, toxins, veterinary drugs, and nutritional
additives in food samples is being investigated with SPR
biosensors [47, 48].
The information about the binding site or 3D structure
of target proteins that is extracted from chemical proteo-
mics approaches can be used for providing virtual hits by
in silico screening of large substance library. Virtual
screening methods have increasingly been used as a com-
plementary means of finding small molecules that are
active with a particular target. In this screening, detailed
knowledge about the binding site of the target protein
provides a promising starting point for finding com-
pounds with selectivity that are suitable as lead candi-
dates and their biological activity can be directly evalu-
ated in in-vivo studies.
Consequently, the contribution of chemical proteo-
mics to the pipeline in drug discovery and development
with its several applications are being deployed in new
ways to boost the efficiency of discovery and develop-
ment, the quality of compounds moving through the
pipeline, and the speed with which higher-quality drug
candidates enter into the clinic.
Conclusion
It is very clear that the success in the development of new
small molecule therapeutics could be decided in the step
to choose a suitable target because a bad choice makes us
waste time and money in competitive drug markets. In
drug discovery and development, chemical proteomics
strongly presents the possibility of speeding up target
identification and getting higher-quality leads in a rapid,
systematic, and comprehensive manner by design, synth-
esis, and application of relevant chemical probes. In this
promising approach, the interplay of chemistry and biol-
ogy drives target selection and lead identification with
integrated strategy; chemistry can provide the critical
technologies in the step to design and synthesize the che-
mical tools, and then, the advanced disciplines such as
cell biology, biochemistry, proteomics, structural biol-
ogy, bioinformatics, and physical chemistry provide pro-
found knowledge of compound selectivity and its interac-
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Arch. Pharm. Chem. Life Sci. 2007, 340, 169 – 177
tion with target proteins. Importantly, the elucidation of
the relevant binding site(s) in a target protein for a bioac-
tive small molecule can provide new strategic applica-
tions for lead finding, lead optimization, and develop-
ment of structure-based drug screening system.
In conclusion, together with technologies developed
in a variety of disciplines and improved chemical and bio-
logical information provided from websites (e. g. Prous
Science Integrity, http://www.prous.com; Discovery Gate,
http://www.discoverygate.com), the advances in chemical
proteomics and its expansion in drug discovery and
development could provide new potential for efficient
discovery of new classes of drugs in the near future.
,
SHK was supported by Chemical Genomics Research Project‘,
Korea Research Institute of Chemical Technology, Republic of
,
Korea and Chemical Genomics R&D Project‘, Ministry of
Science and Technology, Republic of Korea.
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