Affinity selection-mass spectrometry screening techniques
for small molecule drug discovery
D Allen Annis, Elliot Nickbarg, Xianshu Yang, Michael R Ziebell
and Charles E Whitehurst
Affinity selection-mass spectrometry (AS-MS) techniques
assess the binding of candidate molecules to immobilized or
soluble receptors, and these methods are gaining acceptance
in high throughput screening laboratories as valuable
complements to traditional drug discovery technologies. A
diversity of receptor types have been evaluated by AS-MS,
including those that are difficult to screen using traditional
biochemical approaches. AS-MS techniques that couple liquid
chromatography-MS with size-based separation methods,
such as ultrafiltration, gel permeation, or size-exclusion
chromatography, are particularly amenable to the demands of
MS-based screening and have demonstrated the greatest
success across a broad range of drug targets. MS
measurements of receptor function have many of the same
advantages as AS-MS screening and are increasingly used for
drug discovery as well.
Addresses
Schering-Plough Research Institute, 320 Bent Street, Cambridge,
MA 02139, United States
Corresponding author: Annis, D. Allen (allen@allenannis.com),
Nickbarg, Elliot (elliot.nickbarg@spcorp.com), Yang, Xianshu
(xianshu.yang@spcorp.com), Ziebell, Michael R.
(michael.ziebell@spcorp.com) and Whitehurst, Charles E.
(charles.whitehurst@spcorp.com)
Current Opinion in Chemical Biology 2007, 11:518526
This review comes from a themed issue on
Analytical Techniques
Edited by Peter M Fischer
1367-5931/$ see front matter
# 2007 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.cbpa.2007.07.011
Introduction
Mass spectrometry (MS) is one of the most powerful
analytical techniques in modern science, and it plays a
key role in nearly every stage of the drug development
process [1]. Recent advances in MS instrument design,
especially the development of electrospray ionization
(ESI), have extended the reach of MS to the lead discovery
stages of drug development as well. Modern pharmaceu-
tical discovery relies increasingly on target-based screening
techniques to identify new lead compounds for receptors
that have known or suspected involvement in a disease
pathway. High-throughput screening (HTS) methods that
Current Opinion in Chemical Biology 2007, 11:518526
use MS as the detection system are of particular interest
because of the exquisite sensitivity and unique selectivity
possible with MS. In some screening formats, the selec-
tivity achieved by MS enables direct analysis of compound
mixtures such as combinatorial libraries and unpurified
natural products extracts an advantage that is not easily
achieved using other analytical methods. MS-based
screening is primarily implemented in two ways: by
monitoring the functional output of a receptor-dependent
biochemical reaction, or by using affinity-based methods
that directly assess binding of a candidate molecule to its
target receptor. Because of their expanding popularity,
both of these styles of MS-based drug discovery have been
the subject of several timely reviews, special issues of
topical journals, and the focus of at least two recent books
[2,3,47]. Herein we report on the recent contributions to
the field of MS-based drug discovery, with special empha-
sis on lead identification methods that couple an affinity
selection step with MS confirmation of receptorligand
binding.
Affinity selection-MS: direct detection of
receptorligand complexes
Affinity selection-MS (AS-MS) methods directly or
indirectly measure binding of small molecules to their
biomolecular target, and all varieties of AS-MS include
the following steps: (i) an affinity selection stage, where
the protein is equilibrated with one or more potential
ligands, allowing the protein to form a complex with any
compound capable of binding; (ii) the resulting receptor
ligand complexes are separated from non-binding mix-
ture components; and (iii) ligands are identified by MS or
MSMS.
Direct AS-MS methods (Table 1) separate proteinligand
complexes from unbound components within the mass
spectrometer, then measure the mass of the non-covalent
or (less commonly) the covalent proteinligand complex in
the gas phase. Indirect methods (Table 2) use a separation
technique, typically chromatographic in nature, to isolate
the proteinligand complex from unbound components
before MS analysis. Both direct and indirect varieties of
AS-MS have been developed in an assortment of hardware
configurations and successfully applied to screening com-
pound mixtures, including combinatorial libraries and
unpurified natural products extracts.
Researchers at Sunesis developed a fragment-based, direct
AS-MS technique to identify compounds covalently bound
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 Affinity selection-mass spectrometry screening techniques for small molecule drug discovery Annis et al. 519

Table 1

Direct AS-MS screening approaches

Class Method Description Advantages Disadvantages

Covalent Fragment-based Ligand fragments bind
complexes lead assembly covalently to the target
and are identified by MS
Noncovalent Nano-electrospray-MS Gentle ionization High sensitivity permits
complexes technique enables covalent
complexes to be preserved
in the gas phase
Multi-target affinity/ Direct MS detection of
specificity screening noncovalent RNA-ligand
(MASS) complexes
Detection of Direct MS detection of
oligonucleotide-ligand ligands bound to single
complexes by ESI-MS or double stranded
(DOLCE-MS) oligonucleotides
ESI-electron capture The sites of ligand-target
dissociation contacts may be
investigated using ECD
for complexes that remain
intact in the gas phase
Fragment library permits
interrogation of a large
portion of chemical
diversity space
Small molecule library size is
low compound library
concentrations. A high
density chip at the ESI
source increases throughput.
Small sample volumes
Multiple targets may be
screened in the same
sample. Potential to
identify low affinity cmpds
missed by other approaches
Used as counter-screen to
identify ligands with high
affinity to DNA. Automated
sample prep permits >1000
samples/week
Generates data on contact
sites as well as putative
mechanisms of binding.
Appropriate for ligand
optimization efforts
Requires a reactive side chain
in vicinity of binding site.
Assembled fragments may
not generate active compounds
limited and HTS not yet
demonstrated. Gas phase
measurements may not reflect
biological interactions
Mass envelope of ligand-target
complex may not be
observable by spectrometer
No information on specific
oligonucleotide sites of interaction
Useful primarily for high
affinity interactions. May
not work for large complexes
where conformation in the
gas phase is altered

to a target protein [8,9]. In their site-directed ligand
discovery approach, specific amino acids on a protein
surface are modified to facilitate tethering of small mol-
ecule building blocks (fragments). The protein guides
fragment assembly within a binding pocket to select those
building blocks with the best binding characteristics. The
resulting covalent proteinligand complexes are directly
analyzed by MS, and the measured shift in molecular mass
indicates which building blocks yield the best ligand.
Medicinal chemistry efforts, often in conjunction with
X-ray crystallographic analysis, are subsequently employed
to convert the covalently bound fragments into a non-
covalent ligand with better affinity and molecular proper-
ties than the progenitor fragments.
AS-MS techniques that directly interrogate non-
covalent proteinligand complexes are of considerable
value because the resulting leads are inherently more
drug-like than those arising from covalent approaches.
These methods require that the non-covalent com-
plexes survive the transition to the gas phase, and in
1991 Ganem and Henion presented the first conclusive
evidence that the immunosuppressant FK506 and its
biomolecule target FKBP can be directly observed as a
gas-phase complex using ESI-MS as a gentle ioniz-
ation technique [10]. Since this seminal report, many
similar non-covalent receptorligand interactions have
been identified and characterized using ultra-sensitive
nanospray ESI-MS [11,12]. An excellent review was
recently published by Hofstadter and co-workers on
the detection of small molecule DNA and molecule
RNA binding by multi-target affinity/specificity
screening, or multi-target affinity/specificity screening
(MASS) [13]. Zhang and co-workers have commercia-
lized a chip-based ESI-MS system and demonstrated
its utility for studying proteinligand interactions [14].
An especially useful feature of this system is its
ability to quantify binding affinities using a minimal
amount of purified receptor [15]. As an added benefit,
Loo and co-workers have shown that electron capture
dissociation analysis of the proteinligand complex
inside a Fourier transform ion cyclotron mass spec-
trometer can reveal the binding site of a small molecule
on its receptor [16].
ESI-MS methods for detecting receptorligand binding
are appealing because they give direct evidence of the
existence of a complex. However, conflicting data on the
correlation of gas-phase affinity measurements with
solution-phase interactions have been shown [17], in-
cluding reports by researchers using a new, laminar flow
technique that estimates receptorligand affinities by
ESI-MS while not requiring that non-covalent inter-
actions are preserved in the gas phase [18,19]. Also, these
and other related direct AS-MS techniques do not tolerate
high concentrations of non-volatile salts, buffers, cofac-
tors, metal ions, or detergents that may be necessary for
proper protein folding and stability.

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520 Analytical Techniques

Table 2

Indirect AS-MS screening approaches

Class Method Description Advantages Disadvantages

Size exclusion Automated ligand Target-ligand complex
chromatography identification captured by fast sec
and gel permeation system (ALIS) followed by integrated
chromatography LCMS ligand identification
SpeedScreen Target-ligand separation
using 96-well SEC plates
followed by LCMS
Solid phase- Frontal affinity Compounds infused through
immobilized target chromatography a column having a target
with MS detection immobilized on the solid
phase. Weak binders elute
early, strong binders elute later
Affinity capture-MS Compounds combined with
bead-bound target followed
by washing, elution and
detection by ES-MS/MS
Affinity capillary Target-ligand complexes are
electrophoresis-MS separated from other
components by electrophoretic
mobility and bound ligands
identified by MS
Separation by Ultrafiltration-MS Enrichment of target-ligand
ultrafiltration complexes by pressure-based
ultrafiltration, then ligand
dissociation & detection by
ESI-MS
Pulsed Ligand-target complex retained
ultrafiltration-MS on membrane is extracted and
ligands are dissociated and
identified by flow-injection MS
Large mixtures permit HTS.
>10 000 compounds
screened per hour per
instrument
96-well plates permit HTS
(400 000 cmpds/week) when
screened in pools of 400
compounds
Generates affinity ranking
for binders. Controls for
differences in MS sensitivity
between cmpds. (10 000
compounds/day)
Permits interrogation of
protein complexes as
well as poorly solubilized
receptors
Flexible assay format.
Potentially useful for a
range of targets. Short
sample runtimes
Large library mixtures are
possible increasing the
throughput to >200 000
compounds in 2 months
Applicable for targets
with poor chromatography
characteristics when tried
with other separation methods
Samples are processed
linearly (6 min/sample)
limiting HTS of individual
compounds
Total organic content in
bed volume is limited.
Receptor-library separation
is not directly visualized
Protein must be modified
for attachment. Library
size is limited by elution
overlap and competition
Protein must be modified
for attachment.
Background possible due
to nonspecific binding
Ligand must modulate
the target electrophoretic
mobility. Requires volatile
solvents to accommodate
MS
Multiple steps and
incomplete separation
of bound and free
ligands and possibility
of background noise
Ligand binding may be
disrupted by target
interactions with the
membrane. Washing
required

Affinity selection-MS: indirect (hyphenated)
methods
Immobilized ligand or receptor
In part to enable the use of non-volatile buffers in the
receptorligand binding reaction, indirect AS-MS screen-
ing methods have been developed that couple a separ-
ation technique with ESI-MS detection. The simplest
variants are those where one binding partner, either the
receptor or the small molecule ligand, is immobilized on a
solid support. Familiar non-MS methods infer receptor
ligand interactions by measuring changes in surface plas-
mon resonance (Biacore) or wavelength shift (Cornings
EPIC and SRU BioSystems BIND platforms) [20,21].
MS-based techniques detect ligands that have been cap-
tured by an immobilized receptor; for example, Schriemer
and co-workers have developed a frontal affinity chroma-
tography (FAC)-MS platform for lead discovery. In
FAC-MS, a sample containing a set of ligands and a
non-binding marker compound are passed through a
column onto which a receptor has been attached. The
non-binding marker compounds elutes in the void
volume, while each ligand elutes at a later time depend-
ing on its affinity for the immobilized receptor [22,23].
Brennan and co-workers have immobilized nicotinic
acetylcholine receptors on monolithic FAC columns
and confirmed the activity of the bound receptor using
epibatidine as control ligand. In this manner they used
FAC-MS to optimize protein immobilization methods for
on-line enzyme assays [24,25]. Researchers at Protana
have also reported FAC-MS as a global kinase-binding
assay with a throughput of up to 10 000 compounds per
day [26]. They demonstrated their method by discovering
inhibitors of the EphB2 tyrosine kinase receptor, and
described other applications of the platform in a recent
review [27,28]
Affinity capillary electrophoresis (ACE) is a well-estab-
lished technique for drug discovery from complex mix-
tures, including natural products [29]. Despite improved
sensitivity and selectivity by using MS as a detection
system for ACE, it requires the use of volatile buffers in
order to interface with MS, so this application is not
routinely used [30].
Affinity chromatography techniques, including ACE-MS
and FAC-MS, work well for analyzing compound mixtures,

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 Affinity selection-mass spectrometry screening techniques for small molecule drug discovery Annis et al. 521
and can also yield quantitative binding affinity estimates
for a variety of receptor types. Additionally, the affinity
columns can be reused. However, these methods require
that the receptor be immobilized, which can affect its
binding behavior relative to the native, soluble target,
and may cause false positives from compounds binding
non-specifically to the stationary phase or linker system.
While direct MS analysis of the affinity column is chal-
lenged by nonvolatile buffers, integration with matrix-
assisted laser desorption/ionization mass spectrometry
(MALDI-MS) may overcome this limitation [31].
Solution-based methods
Solution-based AS-MS methods do not require immobil-
ization of the target receptor or ligands on a solid support.
This feature avoids the alteration of receptor properties
by tagging or chemical linkage, and it allows greater
compound diversity since immobilizing functional groups
is not necessary. The primary challenge for solution-
based AS-MS methods is the development of efficient
techniques to separate receptorligand complexes from
unbound small molecules.
Separation technologies that use ultrafiltration mem-
branes are commonly used to isolate high molecular
weight biomolecules (>10 kDa proteins and DNA) from
small molecules. Researchers at Abbot used ultrafiltration
to develop an AS-MS screening method by (i) combining
a library of compounds with a protein, then (ii) separating
non-binders by pressure-based ultrafiltration, (iii) re-
equilibrating with library-free buffer and re-separating
by ultrafiltration to enrich higher affinity ligands, and (iv)
denaturing the retained proteinligand complexes and
analyzing the freed ligands by liquid chromatography
(LC)MS [32,33]. These researchers identified hits to
the important oncology targets Bcl-xL and the mamma-
lian checkpoint kinase CHK1, as well as the anti-infective
target Streptococcus enzyme MurF and the oncology target
MetAP2 [34,35,36,37]. A disadvantage of ultrafiltration is
that unbound compounds are not completely removed
unless subsequent washing steps are employed, which
can confound MS detection of true ligands unless they are
significantly enriched relative to chemical noise caused
by unbound compounds. In other reports, Sun and van
Breemen investigated the relative binding of compounds
to estrogen receptors using ultrafiltration-MSMS [38].
Hannewald et al. reported that centrifugal ultrafiltration
followed by MALDI-MS analysis of the retentate
enabled the identification of the control compounds
colchicine, vinblastine and vincristine binding to their
target receptor tubulin [39]. Cheng and van Breemen also
reported an unorthodox, low-throughput AS-MS screen-
ing approach where a ligand-induced increase in target
solubility, in this case A140 from amyloid precursor
protein, was measured by ultrafiltration-based separation
of soluble from aggregated A140 followed by detection
of soluble A140 using flow injection ESI-MS [40]. While
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these latter two reports are interesting examples of ultra-
filtration-based AS-MS, as described these methodologies
are not immediately amenable to HTS.
Gel permeation chromatography (GPC) spin columns are
also used to separate receptorligand complexes from
unbound ligands for AS-MS, and Siegel recently provided
a detailed review of this approach as practiced by Amgen,
Novartis, and Wyeth Pharmaceuticals [41]. A limitation of
this approach is that spin-column handling and centrifu-
gation may be more difficult to automate and scale than
other methods; however, overall throughput can be
increased by pooling the eluants from several spin col-
umns before ESI-MS analysis. Mayr recently reviewed
the successful use of SpeedScreen, an AS-MS method
developed at Novartis that uses a centrifuged 96-well
plate assembly of GPC columns, including a top sample
loading plate with pinholes in the bottom of each well; a
central filter plate pre-loaded with GPC resin (Sephadex,
Pharmacia); and a bottom collection plate for the capture
of effluents containing separated receptorligand com-
plexes [42]. Brown et al. reported on the chemical nature
of hits identified from the SpeedScreen-based HTS of 26
targets [43]. They concluded that SpeedScreen yields
compounds with drug-like properties, albeit with greater
lipophilicity and higher molecular weights than the pro-
genitor compound screening library. The authors empha-
sized the value of using cheminformatic-based filters to
eliminate promiscuous binders, false positives, and dis-
favored chemotypes from primary hit lists, and further
emphasized the importance of hit validation by rigorous
follow-up SpeedScreen assays.
Size exclusion chromatography (SEC) separates protein
ligand complexes from non-binding small molecules by the
same principles as GPC. However, SEC holds several
advantages relative to the spin-column method, including
its amenability to automation and the ability to directly
couple the SEC stage with an LCMS system for ligand
detection. The first fully integrated SEC-LCMS platform
for HTS was developed by researchers at NeoGenesis
(later acquired by Schering-Plough) and dubbed the auto-
mated ligand identification system, or ALIS [44]. The
ALIS process includes the following steps (see Figure 1): a
target receptor plus compound mixture are first combined
in a 96-well plate format and allowed to reach equilibrium,
then the plate is loaded into a chromatography system
fitted with a reusable SEC column containing a proprietary
resin for rapid separation (<20 s) of target-ligand com-
plexes from unbound pool components. Proteinligand
complexes in the SEC eluant are monitored by UV detec-
tion, and an automated valving system directs the protein
peak to a reverse-phase chromatography column for dis-
sociation, desalting, and elution of any ligands into an ESI-
MS system for identification. The ALIS platform has been
used to screen a variety of target classes, including integral
membrane proteins (Table 3). A collaboration between
Current Opinion in Chemical Biology 2007, 11:518526
522 Analytical Techniques

Figure 1

Schematic diagram of the ALIS process.

NeoGenesis and Merck yielded a novel inhibitor for the
protease -Secretase, an important target for Alzheimers
disease therapy [45]. Whitehurst et al. reported on the use
of ALIS to screen the muscarinic M2 acetylcholine re-
ceptor (M2R), a G-protein coupled receptor (GPCR)
[46]. This report was the first to describe screening an
integral membrane receptor by solution-based AS-MS [47].
Beyond HTS, the ALIS platform has been demonstrated
to be a valuable analytical tool for characterizing protein
ligand interactions [48]. For example, saturation bind-
ing assays can be performed where a receptor preparation
at constant concentration is titrated with increasing con-
centrations of a ligand and then analyzed by ALIS to
provide absolute binding affinity estimates and to assess
the quality of different protein preparations. ALIS
enables the simultaneous detection of multiple target-
bound ligands in a single binding reaction, allowing the
determination of allosteric or isosteric competitive bind-
ing profiles versus known ligands or cofactors, while also
providing mixture-based affinity measurements that
enable potency optimization and the development of
structureactivity relationships directly from combinator-
ial chemical libraries [49]. These ALIS-based analytical
techniques were highlighted in the report of the ALIS-
based screening of M2R, where ALIS was applied to
three phases of lead discovery: (i) biochemical validation
of the target before HTS screening; (ii) HTS screening of
a diverse combinatorial small molecule library; and (iii)
the characterization of newly discovered hits to determine

Table 3

Protein types screened by solution-based AS-MS

SEC-RPC-ESI-MS GPC Spin FAC-ESI-MS Ultrafiltration-ESI-MS

column-ESI-MS or -MALDI-TOF-MS
Schering-Plough, Amgen, Novartis, Protana Abbott, Van
Merck Wyeth Breemen
Kinases U U U U
Proteases, peptidases U U U U
Other enzyme classes U U U U
Nuclear hormone receptors U U U U
Protein complexes U
GPCRs, integral membrane proteins U
Proteinprotein interaction targets U U U U
Transcription factors U U

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 Affinity selection-mass spectrometry screening techniques for small molecule drug discovery Annis et al. 523
if any are interesting leads [46]. Interestingly, the ALIS-
based screening of M2R resulted in the discovery of both
orthosteric antagonists and a putative allosteric modu-
lator, consistent with the proposed capability of AS-MS to
discover ligands with various binding modes for a receptor
[50].
To date, Schering-Plough is the only company to have
reported the routine use of on-line SEC-LCMS for
HTS. However, several proof-of-concept studies have
been reported recently that demonstrate other appli-
cations of on-line SEC-LCMS. For example, Flarakos
and Vouros reported that custom-made SEC columns
packed with Sephadex G-25 media (to mimic centrifugal
spin-columns) could be connected by an on-line switch-
ing system to UV-based detectors, enabling protein
ligand complex monitoring and capture for LCMS
detection of bound ligandsin this case, compounds that
bound to human serum albumin [51]. These investigators
reported that improvements in miniaturization are
required to reduce protein and compound consumption
in their system to enable HTS. Researchers at Merck
recently described an integrated SEC-LCMS platform
to affinity-rank ligands present in mixtures by competi-
tive affinity selection to dipeptidyl peptidase IV [52].
They showed that the relative affinities of the ligands
determined by their AS-MS technique corresponded well
with the known relative biochemical IC50 values of the
ligands, but did not report on HTS efforts.
MS measurements of receptor function
MS-based techniques that monitor functional assays have
advantages that parallel those of AS-MS. Target-based
functional assays identify lead compounds by measuring
the outcome of a biomolecule-mediated transformation,
such as production or depletion of the starting materials or
products of an enzymatic reaction, or displacement of a
labeled marker compound from a biomolecular receptor.
These measurements are traditionally done using radio-
chemical methods, fluorescence readouts, or UV spec-
troscopy. By using MS analysis, the products of enzymatic
reactions or displaced ligands can be directly identified by
virtue of their molecular mass, which eliminates chemical
interferences and obviates the need for radioactive or
fluorescent labeling of compounds or marker agents.
A considerable challenge to MS-based functional screen-
ing is that most assays require high concentrations of salts,
buffers, cofactors or detergents, which are nonvolatile
components that interfere with MS analysis coupling
LC with the mass spectrometer enables nonvolatile com-
ponent removal, and Wanner and co-workers used this
capability to develop competitive MS-binding assays
[53,54]. In this system, LCMS detection is used to assess
the ability of test compounds to compete a native (non-
labeled) marker ligand from its pharmacological receptor,
by either analyzing the free (unbound) marker or by
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quantifying the bound marker after sequential filter iso-
lation and liberation steps. Fragmentation of the marker
in a triple quadrupole MS and quantitation of the result-
ing MSMS ions relative to an isotopically labeled (but
non-radioactive) standard yielded excellent reproducibil-
ity and good correlation with results from a traditional
radioligand analysis [55].
Throughput can also be a challenge for MS-based func-
tional screening. Despite the advent of multi-head injec-
tors for sequential switching between LC-purified
samples, MS is an inherently serial analysis technique,
since only one sample at-a-time can be introduced to the
mass analyzer. (This contrasts with UV- or fluorescence-
based spectroscopic techniques, where array detectors
allow simultaneous measurement from many samples.)
To overcome this limitation, researchers at BioTrove have
developed an ultra-fast sample switching inlet for a triple-
quadrupole mass spectrometer, and commercialized its
application for monitoring enzyme reaction products by
LCMS. Their Rapid Fire system can analyze over
10 000 samples in a day, and was demonstrated by the
discovery of several potent inhibitors of acetylcholinester-
ase, the Akt1 kinase, and the membrane-associated protein
phosphatidylserine decarboxylase (PISD) [56,57,58].
In another approach to automated MS-based enzyme
assays, Brennan and co-workers have developed a sol
gel entrapment system to immobilize proteins for on-line
inhibitor screening [59]. By eluting enzyme substrates
plus possible inhibitors over the trapped proteins, these
researchers measure the effect of the inhibitor on enzyme
activity or receptor binding, as exemplified by a screen of
49 compounds against adenosine deaminase (ADA) with
IC50 determination for active inhibitors. They have
demonstrated the entrapment technique for a variety
of target systems, including membrane proteins such as
the nicotinic acetylcholine receptor (nAChR) and dopa-
mine D2 receptor [60].
Enzyme inhibitors have also been characterized in high-
throughput fashion by MALDI-MS techniques, in-
cluding desorption/ionization on silicon (DIOS-MS)
[61] and from carbon nanotube-based matrices [62]. A
particular advantage of the MALDI approach is demon-
strated by its application in kinase assays. Traditionally
the phosphorylation of a protein or substrate is monitored
by incorporation of radioactive phosphate into the pro-
duct. MALDI-MS allows modification of the native sub-
strate even whole proteins to be monitored directly
without the use of a labeled probe [63]. Unfortunately,
these approaches are limited to use with volatile buffers,
for example, ammonium carbonate.
Conclusions and future directions
As shown in this report, the pharmaceutical industry
is enthusiastically using MS-based HTS methods to
Current Opinion in Chemical Biology 2007, 11:518526
524 Analytical Techniques
discover and characterize new lead compounds, and we
anticipate these applications will continue and expand in
the future. Presently, no one-size-fits-all AS-MS solution
is expected to satisfy all future screening demands, and no
commercial product specifically tailored for AS-MS
screening is available to interested researchers. Rather,
a diversity of methods is implemented by different com-
mercial and academic laboratories, each with its particular
advantages and disadvantages, suggesting that no single
technique can solve the broad range of requirements that
modern pharmaceutical discovery requires. As analytical
instrumentation becomes miniaturized and more auto-
mated, especially MS and LC components, their ease of
use for non-specialists will naturally allow more wide-
spread and creative applications and may expand the
already considerable impact of AS-MS on drug discovery.
Acknowledgements
We thank Satish Jindal, Jerry Shipps, Arshad Siddiqui, and our
colleagues at SPRI for critical review of this manuscript.
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