ANALYSIS

Trends in the exploitation of novel

drug targets
Mathias Rask-Andersen*, Markus Sllman Almn* and Helgi B.Schith*
Abstract | The discovery and exploitation of new drug targets is a key focus for both the
pharmaceutical industry and academic biomedical research. To provide an insight into
trends in the exploitation of new drug targets, we have analysed the drugs that were
approved by the US Food and Drug Administration during the past three decades and
examined the interactions of these drugs with therapeutic targets that are encoded by the
human genome, using the DrugBank database and extensive manual curation. We have
identified 435 effect-mediating drug targets in the human genome, which are modulated
by 989 unique drugs, through 2,242 drugtarget interactions. We also analyse trends in the
introduction of drugs that modulate previously unexploited targets, and discuss the network
pharmacology of the drugs in our data set.

*Department of Neuroscience,
Functional Pharmacology,
Uppsala University,
Uppsala Biomedical Center,
75124 Uppsala, Sweden.
Understanding the identity of drug targets that are
encoded by the human genome is of great importance
for the development of new pharmaceutical products
and the allocation of resources within academic and
industrial biomedical research. Currently marketed
drugs mediate their effects through only a small num-
ber of the potential human target proteins. Previously
published estimates of the number of current human
drug targets range from ~200400, depending on the
method used and how the drug targets were defined and
categorized.
In 1996, Drews and Ryser were the first to present
an overall estimate of the number of target proteins in
humans and pathogens when they put forward an esti-
mate of 483 drug targets, based on an analysis of drugs
listed in the ninth edition of The Pharmacological Basis
of Therapeutics1. They also estimated that the number of
potential drug targets in the human genome was ~5,000
10,000, which was influenced by the view at the time that
the human genome contained ~300,000 genes1,2.
After the sequencing of the human genome, Hopkins
and Groom3 estimated that there were 120 drug targets
for marketed small-molecule drugs, by analysing the
Investigational Drugs database and Pharmaprojects
estimated to contain ~30,000 genes and, of these, ~3,000
genes were suggested to be linked to disease based on
the extrapolation of data from the number of antifungal
targets in the yeast genome. The overlap between the
two sets of genes estimated to be ~6001,500 genes
in total3 was suggested to represent the number of
pharmacologically exploitabletargets.
In 2006, Imming etal.4 listed 218 drug targets for
approved drugs, using by their own terms some-
what arbitrary definitions for drug targets and drug
categories, which led to a lower estimate in compari-
son. Also in 2006, Overington etal.5 estimated that the
human genome contained 266 proteins that could be
targeted by pharmacological agents. They were able to
assign a total of 324molecular targets to 1,065 phar-
macological agents through a systematic review of the
US Food and Drug Administration (FDA) Orange Book
and the Center for Biologics Evaluation and Research
(CBER) website. This analysis led to the identification of
21,000 active agents, but only 1,357 unique drugs when
redundant formulations and non-therapeutic agents
were removed5.
The publicly available DrugBank database, which
drew heavily from these earlier data sets, was launched

Department of Neuroscience,
Uppsala Biomedical Center,
BOX593, 75124 Uppsala,
Sweden.
Correspondence to H.B.S.
email: helgi.schioth@neuro.
uu.se
doi:10.1038/nrd3478
databases. In total, they identified 399 targets for which
ligands with drug-like properties (regardless of whether
or not they were approved drugs) were known. By
expanding from members of the 130 protein families that
were found to be drug targets, they also estimated
that ~10% of all genes in the genome were pharma-
cologically tractable. In 2002, the human genome was
in 2006. The DrugBank database not only has a sys-
tematic collection of drugprotein interactions but
also contains associations of proteins with consensus
genetic annotations, such as Swissprot. The DrugBank
database has been expanded by ~60% since its release to
include further FDA-approved and experimental drugs,
as well as data for almost 1,000 additional drugtarget

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A N A LY S I S

interactions68. The database currently contains infor- drugtarget interactions were removed because the
mation on ~1,500 experimental, approved and with- majority of these interactions were either irrelevant from
drawn drugs, with up to 107 data fields for each drug a disease-treatment perspective or part of the side-effect
that contain information including current indications, profile of the pharmacological agent. We therefore per-
documented drugtarget interactions, target protein formed a manual curation of the database to achieve
accession numbers and pharmacologicalactions. a reproducible data set of human genes encoding the
In this article, we have analysed the complete data target proteins that are responsible for the desired phar-
set of pharmacological agents as of May 2009 from macological effects. We also manually curated entries for
the DrugBank database (see FIG.1 for an overview of the indications and classified proteins according to molecu-
analysis process). Annotations in the DrugBank data- lar function using their Swissprot accession numbers.
base that were related to the functional relevance of We retrieved drug approval dates from the FDA and
linked these to the drugs in our curated data set to iden-
tify trends in drug development. We manually added
0WODGT FDA-approved drugs and drug targets from 20072010
&TWIDCPMFCVCDCUG &TWIECVGIQT[
FTWIU 7PMPQYPOGEJCPKUO  into our data set, to account for lag times between the
&KTGEV&0#KPVGTCEVKPI  introduction of a new drug and its incorporation into the
#PVKDKQVKE  DrugBank database. In contrast with previous publica-
4GOQXCNQHFTWIU FTWIU #OKPQCEKF  tions in this field, we also provide a specific list of the
YKVJPQMPQYPVCTIGV drugs (see Supplementary information S1 (table)) to aid
&KGVCT[UWRRNGOGPV 
1VJGT  further analyses.
6QVCN 
FTWIUCEVKPIQP Drugs and classes of drug targets
RTQVGKPVCTIGVU The initial curation of the data set involved the identi-
6CTIGVECVGIQT[ 0WODGT fication of drugs without known protein targets, such
$CEVGTKC  as drugs that act directly on DNA, dietary supplements
4GOQXCNQHFTWIU
YKVJPQJWOCPVCTIGV
FTWIU #PKOCNU  and drugs that do not have known protein targets. This
8KTWUGU  resulted in a list of 1,317 drugs that act on 1,236 protein
2CTCUKVGU  targets. We also identified drugs that were administered
(WPIK  as prodrugs and were therefore already present in the
FTWIUCEVKPIQP 'WT[CTEJCGQVC  data set in their active form, and we identified drugs
JWOCPRTQVGKPVCTIGVU
6QVCN  that act on non-human target genes, such as antibiotics,
antiparasitics and antifungals.
4GOQXCNQHPQP This specification resulted in a list of 1,092 pharma-
VJGTCRGWVKEVCTIGVU PQPVJGTCRGWVKEVCTIGVU cological agents that act on 1,044 human protein targets.
We then identified the genes encoding non-therapeutic
FTWIUYKVJQWVMPQYP
protein targets (for example, albumin or cytochrome P450
FTWIUCEVKPIQP
VJGTCRGWVKEGGEV VJGTCRGWVKEVCTIGVU enzymes), as well as agents without therapeutic targets.
OGFKCVKPIVCTIGVU We used a row-by-row approach in favour of automated
methods in which each drug, drug target and interac-
tion was evaluated and validated using current medical
literature and publicly available databases. The main
effect-mediating targets were identified manually for each
6QRFTWIKPFKECVKQPU 0WODGT 6CTIGVENCUU 0WODGT drug and therapeutically irrelevant targets or side effect-
#PVKJ[RGTVGPUKXGCIGPVU  4GEGRVQTU  mediating targets were identified in the data set. This was
#PVKPGQRNCUVKECIGPVU  'P\[OGU  performed in an effort to create a data set with strictly
#PVKKPCOOCVQT[CIGPVU  6TCPURQTVGTU  defined active targets, which could be useful for further
*[RPQVKEUCPFUGFCVKXGU  1VJGT  bioinformatics analysis of the therapeutic portion of the
#PVKCNNGTIKECIGPVU  druggable genome as well as for novel target prediction.
#PVKEQPXWNUCPVU  Through this strict manual curation of the DrugBank
#PVKCTT[VJOKCCIGPVU  database (FIG.1), we identified 435 effect-mediating drug
#PVKRU[EJQVKECIGPVU  targets in the human genome. These structures are the
#PVKFGRTGUUCPVU  targets of 989 unique drugs, through 2,242 drugtarget
#PCNIGUKEU  interactions (see Supplementary informationS1 (table)).
The DrugBank database lists indications for each
Figure 1 | Data curation process. Data were collected from the DrugBank database drug, and these were also validated in the curation
0CVWTG4GXKGYU^&TWI&KUEQXGT[
as of May 2009 and curated manually to identify drugs without known targets and drugs
process. The most common indication for the drugs
that target gene products of pathogens, such as antiparasitics, antivirals and antibiotics.
Specific human gene products that encode therapeutic drug targets were also identified in our data set is antihypertensive drugs, followed by
manually among the drugtarget interactions. Primary and secondary indications of the antineoplastic and anti-inflammatory agents. Each
drugs were identified by manually curating interaction entries. Drugs and drug targets target-encoding gene was assigned a class according
that were approved by the US Food and Drug Administration between 2007 and 2010, to the molecular function of the gene product using
and were not included in the Drugbank database, were added manually. the Swissprot accession numbers. Our curated data set

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 A N A LY S I S

shows that receptors make up the largest group of drug
targets: 193 proteins (44% of the human drug targets)
are receptors, and 82 (19%) of these are G protein-cou-
pled receptors (GPCRs). In the overall data set, ~36%
of drugs target GPCRs (FIG.2). GPCRs have been com-
monly targeted by antihypertensive and anti-allergic
drugs. Ligand-gated ion channels, which are the second
largest receptor target class, are most commonly targeted
by hypnotic drugs and sedatives. The third largest recep-
tor target class, receptor tyrosine kinases such as the
epidermal growth factor receptor have been targeted
frequently by anticancer drugs (intracellular non-recep-
tor kinases, such as ABL, the active site of which is the
target of imatinib,are classifiedas enzymes).
Enzymes are the second largest group of target pro-
teins in the human genome, with 124 target-encoding
genes, comprising 29% of all human drug targets (FIG.2).
Hydrolases (EC3) are the most common class of enzy-
matic drug targets, comprising 42% of all human enzyme
drug targets. They are followed by oxidoreductases (EC1)
and transferases (EC2), which comprise 27% and 19% of
all human enzyme drug targets, respectively. In addition,
the majority (78%) of enzyme targets are soluble proteins,
not membrane-associated proteins. Anti-inflammatory
treatments most frequently act on enzyme targets; for
example, the most studied anti-inflammatory target path-
way the eicosanoid metabolic pathway is modulated
via the enzyme targets cyclooxygenase 1 and cyclooxyge-
nase 2, which belong to the oxidoreductase family and are
targeted by acetylsalicylic acid. Other common enzyme
targets for drugs include DNA polymerases, angiotensin-
converting enzyme and the monoamine oxidases.

6CTIGVENCUU 0WODGTQHRTQVGKPU /QUVEQOOQPVJGTCRGWVKECEVKQPU 0WODGT

QHFTWIU

4GEGRVQTU  #PVKJ[RGTVGPUKXGCPVKCNNGTIKE 

)RTQVGKPEQWRNGFTGEGRVQTU  #PVKJ[RGTVGPUKXGCPVKCNNGTIKE 
.KICPFICVGFKQPEJCPPGNU  *[RPQVKECPFUGFCVKXGCPVKEQPXWNUCPV 
4GEGRVQTV[TQUKPGMKPCUGU  #PVKPGQRNCUVKEXCUQFKNCVQT 
+OOWPQINQDWNKPNKMGTGEGRVQTU  +OOWPQOQFWNCVQT[CPVKPGQRNCUVKE 
1VJGTTGEGRVQTU  +OOWPQOQFWNCVQT[RNCVGNGVCIITGICVKQP 
0WENGCTTGEGRVQTU  #PVKPGQRNCUVKEJQTOQPGTGRNCEGOGPV 

'P\[OGU 
 #PVKKPCOOCVQT[CPVKPGQRNCUVKE 
'%1ZKFQTGFWEVCUGU 
 #PVKKPCOOCVQT[CPVKPGQRNCUVKE 
'%6TCPUHGTCUGU 
 #PVKPGQRNCUVKEDKURJQURJQPCVG 
'%*[FTQNCUGU 
 #PVKJ[RGTVGPUKXGXCUQFKNCVQT 
'%.[CUGU 
 #PVKJ[RGTVGPUKXGFKWTGVKE 
'%+UQOGTCUGU 
 #PVKPGQRNCUVKEKOOWPQUWRRTGUUKXG 
'%.KICUGU 
 #PVKPGQRNCUVKECPVKDTKPQN[VKE 
/WNVKRNG'%ITQWRU 
 #PVKPGQRNCUVKECPVKCFTGPCN 

6TCPURQTVGTRTQVGKPU  #PVKJ[RGTVGPUKXGCPVKCTTJ[VJOKC 

8QNVCIGICVGFKQPEJCPPGNU  #PCGUVJGVKECPVKCTTJ[VJOKC 
1VJGTKQPEJCPPGNU  #PVKJ[RGTVGPUKXGFKWTGVKE 
5QNWVGECTTKGTU  #PVKJ[RGTVGPUKXGFKWTGVKE 
#EVKXGVTCPURQTVGTU  #PVKJ[RGTVGPUKXGCPVKWNEGT 
1VJGTVTCPURQTVGTU  *[RPQVKECPFUGFCVKXGCPVKCPZKGV[ 
#WZKNNCT[VTCPURQTVWPKVU  #PVKJ[RGTVGPUKXGXCUQFKNCVQT 

1VJGT  #PVKKPCOOCVQT[CPVKPGQRNCUVKE 
'P\[OGKPVGTCEVKPIRTQVGKPU  #PVKKPCOOCVQT[INWEQEQTVKEQKF 
5VTWEVWTCNCPFCFJGUKQPRTQVGKPU  #PVKPGQRNCUVKE 
.KICPFU  #PVKTJGWOCVKE 
1VJGT  #PVKKPCOOCVQT[CPVKPGQRNCUVKE 

Figure 2 | Classification of the currently utilized drug targets that are encoded by 0CVWTG4GXKGYU^&TWI&KUEQXGT[
the human genome. The class
of drug target was determined by using the Swissprot accession number of the corresponding therapeutic target of each
drug. The most common indications for each class are listed, as well as the corresponding number of drugs that target
each protein class. *Enzymes are further classified as soluble or membrane-associated; the number in the brackets
corresponds to the number of membrane-associated enzymes in each class.

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 A N A LY S I S
C 
0/'UCRRTQXGFRGT[GCT
0/'UVCTIGVKPIGP\[OGU
0/'UVCTIGVKPITGEGRVQTU

0/'UVCTIGVKPIVTCPURQTVGTU
0/'UCRRTQXGFRGT[GCT



              
D from our analysis). It is apparent from these data that
06&U 06&UVCTIGVKPITGEGRVQTU
06&UVCTIGVKPIGP\[OGU 06&UVCTIGVKPIVTCPURQTVGTU

06&UCRRTQXGFRGT[GCT
 in the approval rate of novel target drugs (NTDs)
 cally during thisperiod.
              
Figure 3 | Number of new drugs affecting targets that are encoded by the human
genome, and drugs affecting previously unexploited0CVWTG4GXKGYU^&TWI&KUEQXGT[
targets, that were approved
by the FDA from 19832010. Approval dates were retrieved from the catalogue of US
Food and Drug Administration (FDA) Approved Drug Products (see the Drugs@FDA
website). Drugs were divided into subcategories according to a general classification of
their target structure (a) and whether the drug acts on a previously exploited or
unexploited (novel) target structure in the human genome. The number of drugs with novel
targets (NTDs) overall and in the target subcategories is shown in panel b. Three innovation
peaks are apparent in this panel: 19901993, 19942000 and 20012008. These
innovation peaks are discussed in detail in the section 30years of drug target
innovation. NMEs, new molecular entities.
Transporter proteins are the third most common class
of targets, with 67 target-encoding genes that comprise
15% of all human drug targets (FIG.2). These proteins
facilitate the movement of specific substrates such as ions,
nutrients and metabolites across lipid membranes. This
category encompasses voltage-gated ion channels, active
transporters and solute carriers among other transporter
proteins, and is commonly targeted by antihypertensive
drugs, diuretics, anaesthetics and anti-arrhythmic drugs.
Voltage-gated ion channels, which are often targeted by
anaesthetics and anti-arrhythmic drugs, are the most
common type of transporter drug target (FIG.2).
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2011 Macmillan Publishers Limited. All rights reserved
30years of drug target innovation
To determine trends in drug development, we accessed
drug approval dates from the FDA, via the Drugs@FDA
website and the FDA Orange Book. We were able to
determine the FDA approval date for 747 drugs. Drugs
that were approved before 1982 were omitted from fur-
ther analysis owing to a cut-off point in the Orange Book
for drugs that were approved before this date, leaving
520 drugs that were approved from 1982 until the end
of 2010 (FIG.3a).
On average, we found that ~18 (17.9) new drugs tar-
geting human proteins have been approved for market-
ing by the FDA every year, of which ~4 (4.3) act on novel
target structures that are encoded by the human genome,
which corresponds well to previously reported figures
by Yildirim and colleagues9. However, our estimates are
slightly lower, which is most likely to be due to our focus
on human genome targets (for example, novel virus-
encoded targets for diseases such as HIV were excluded
the majority of new drugs that have been approved since
1982 act on previously exploited human proteintargets.
There was no apparent decrease in the rate of
approval of new drugs targeting structures encoded by
the human genome between 1982 and 2010, according
to our data set (linear regression was performed in Prism
v5.02 for Windows, GraphPad Software, Inc. San Diego).
Interestingly, we also did not observe an overall decrease
that is, drugs that act on previously unexploited targets
encoded by the human genome (TABLE 1). The rate of
innovation in terms of the exploitation of drug targets
thus appears to be stable over the past 30years, although
it should be noted that the research and development
investment made to achieve this has increased dramati-
The innovation rate for NTDs has a pulsing appear-
ance, with three distinct innovation peaks (FIG.3b).
There are some interesting similarities and differences
between the approvals comprising these peaks. For
example, the first observed peak between 1990 and
1993 is shorter than the others, but NTD approvals for
the most common types of targets GPCRs, hydro-
lases, transferases and isomerases occurred at a pro-
portionally similar rate to other peaks. NTDs that were
introduced during this period include ondansetron,
an anti-emetic selective 5hydroxytryptamine receptor
3 antagonist (approved in 1991), and the asthma ther-
apy nedocromil (approved in 1992), which targets the
cysteine leukotriene receptor 1. Although the majority
of NTDs modulate targets in previously exploited areas of
the proteome, there is also a trend towards an increase
in the number of protein types that are targeted by NTDs in
the later two innovation peaks. For example, during the
period of the second innovation peak (19942000),
the first drug that targeted integrins the cardiovas-
cular drug abciximab (approved in 1997) was intro-
duced. During the period of the third innovation peak
(20012008), the first kinase inhibitor for treating cancer
(imatinib; approved in 2001) and the first drug targeting
Fc receptors (the asthma drug omalizumab; approved in
 A N A LY S I S

Table 1 | Introduction of drugs with new human genome-encoded targets

Drug Target Therapeutic class Year of Drug classification
gene* approval
New drugs introduced: 19831989
Bumetanide SLC12A2 Diuretics 1983 Small molecule
Divalproex sodium ABAT Anticonvulsant agents, antimanic agents 1983 Small molecule
Indapamide KCNE1 Antihypertensive agents, diuretics 1983 Small molecule
Etoposide TOP2A Antineoplastic agents 1983 Small molecule
Cyclosporine PPP3R2 Immunosuppressive agents 1983 Small molecule; fungal extract
Bentiromide PNLIP Diagnostic agents 1983 Small molecule
Amrinone PDE4B Cardiotonic agents, 1984 Small molecule
phosphodiesterase inhibitors
Trilostane HSD3B1 Antiadrenal agents 1984 Small molecule (now withdrawn)
Auranofin IKBKB Antirheumatic agents 1985 Small molecule
Marinol CNR1 Anti-emetic agents 1985 Small molecule
Cilastatin DPEP1 Adjuvants, enzyme inhibitors 1985 Small molecule
Muromonab CD3E Immunosuppressive agents 1986 Biotechnological; monoclonal antibody
Interferon alfa-2a IFNAR1 Antineoplastic agents, 1986 Biotechnological; recombinant protein
(recombinant) immunomodulatory agents
Urofollitropin FSHR Fertility agents 1986 Biotechnological; recombinant protein
Tranexamic acid PLAT Antifibrinolytic agents 1986 Small molecule
Terazosin ADRA1D Antineoplastic agents, antihypertensive 1987 Small molecule
agents
Lovastatin HMGCR Anticholesteraemic agents 1987 Small molecule
Teriparatide PTHR1 Diagnostic agents 1987 Biotechnological; synthetic peptide
Octreotide SSTR1 Hormonal antineoplastic agents, 1988 Biotechnological; hormone;
hormone replacement agents synthetic peptide
Nicardipine CACNA1C Anti-arrhythmia agents, 1988 Small molecule
antihypertensive agents
Selegiline MAOB Antiparkinson agents 1989 Small molecule
Epoetin alfa EPOR Anti-anaemic agents 1989 Biotechnological; recombinant protein
Omeprazole ATP4A Gastrointestinal anti-ulcer agents 1989 Small molecule
Propafenone KCNH2 Anti-arrhythmia agents 1989 Small molecule
New drugs introduced: 19901999
Bepridil CACNA1A Anti-arrhythmia agents, 1990 Small molecule
antihypertensive agents
Sermorelin GHRHR Hormone replacement agents 1990 Biotechnological; hormone; synthetic
peptide
Ondansetron HTR3A Anti-emetic agents 1991 Small molecule
Filgrastim CSF3R Antineutropaenic agents 1991 Biotechnological; recombinant protein
Sargramostim CSF2RA Immunomodulatory agents 1991 Biotechnological; recombinant protein
Fludarabine POLA1 Antineoplastic agents 1991 Small molecule
Pentostatin ADA Antineoplastic agents 1991 Small molecule
Pamidronate FDPS Bisphosphonates 1991 Small molecule
Ticlopidine P2RY12 Platelet aggregation inhibitors 1991 Small molecule
Botulinum toxin SNAP25 Neuromuscular blocking agents 1991 Biotechnological; bacterial extract
type A
Finasteride SRD5A1 Anti-baldness agents, 1992 Small molecule
antihyperplasia agents
Amlodipine CACNA1B Antihypertensive agents 1992 Small molecule
Paclitaxel TUBB1 Antineoplastic agents 1992 Small molecule

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Table 1 cont. | Introduction of drugs with new human genome-encoded targets

Drug Target Therapeutic class Year of Drug classification
gene* approval
Nedocromil CYSLTR1 Anti-allergic agents, anti-asthmatic agents 1992 Small molecule
Cisapride HTR4 Parasympathomimetic agents 1993 Small molecule (now withdrawn)
Abciximab ITGB3 Anticoagulants, antiplatelet agents 1993 Biotechnological; monoclonal antibody
Tacrolimus FKBP1A Immunosuppressive agents 1994 Small molecule
Candoxatril MME Antihypertensive agents 1995 Small molecule
Metformin PRKAB1 Hypoglycaemic agents 1995 Small molecule
Losartan AGTR1 Antihypertensive agents 1995 Small molecule
Mycophenolate IMPDH2 Immunosuppressive agents 1995 Small molecule
mofetil
Acarbose AMY2A Hypoglycaemic agents 1995 Small molecule
Amifostine ALPPL2 Radiation-protective agents 1995 Small molecule
Topotecan TOP1 Antineoplastic agents 1996 Small molecule
Latanoprost PTGFR Glaucoma treatment, intraocular hypertension 1996 Small molecule
treatment
Arcitumomab CEACAM1 Diagnostic agents, imaging agents 1996 Biotechnological; monoclonal antibody
Pentosan polysulfate FGF1 Anticoagulants 1996 Small molecule
Capromab PSMA Diagnostic agents 1996 Biotechnological; monoclonal antibody
Reteplase PLG Thrombolytic agents 1996 Biotechnological; recombinant protein
Topiramate CA2 Anticonvulsants, antimigraine agents 1996 Small molecule
Troglitazone PPARG Hypoglycaemic agents 1997 Small molecule
Imiquimod TLR7 Immunomodulatory agents 1997 Small molecule
Ardeparin SERPIND1 Anticoagulant agents 1997 Small molecule
Tiagabine SLC6A1 Anticonvulsant agents 1997 Small molecule
Oprelvekin IL11RA Thrombotic agents 1997 Biotechnological; recombinant protein
Rituximab MS4A1 Antineoplastic agents 1997 Biotechnological; monoclonal antibody
Fomepizole ADH1B Antidotes 1997 Small molecule
Becaplermin PDGFRB Topical anti-ulcer agents 1997 Biotechnological; recombinant protein
Daclizumab IL2RA Immunosuppressive agents 1997 Biotechnological; monoclonal antibody
Tolcapone COMT Antiparkinson agents 1998 Small molecule (now withdrawn)
Infliximab TNF Immunosuppressive agents 1998 Biotechnological; monoclonal antibody
Leflunomide DHODH Antirheumatic agents 1998 Small molecule
Trastuzumab HER2 Antineoplastic agents 1998 Biotechnological; monoclonal antibody
Thyrotropin alfa TSHR Diagnostic agents 1998 Biotechnological; recombinant protein
Interferon gamma-1b IFNGR1 Immunomodulatory agents 1999 Biotechnological; recombinant protein
Sirolimus FRAP1 Immunosuppressive agents 1999 Small molecule
Epirubicin CHD1 Antineoplastic agents 1999 Small molecule
Orlistat LIPF, PNLIP Anti-obesity agents 1999 Small molecule
New drugs introduced: 20002010
Gemtuzumab CD33 Antineoplastic agents 2000 Biotechnological; monoclonal antibody
ozogamicin conjugate (now withdrawn)
Botulinum toxin VAMP1 Neuromuscular blocking agents 2000 Biotechnological; bacterial extract
type B
Alemtuzumab CD52 Antineoplastic agents 2001 Biotechnological; monoclonal antibody
Imatinib
BCRABL Antineoplastic agents 2001 Small molecule
fusion
Anakinra IL1R1 Antirheumatic agents 2001 Biotechnological; recombinant protein
Bosentan EDNRB Antihypertensive agents 2001 Small molecule

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 A N A LY S I S

Table 1 cont. | Introduction of drugs with new human genome-encoded targets

Drotrecogin alfa F8 Antithrombotic agents 2001 Biotechnological; recombinant protein
Drug Target Therapeutic class Year of Drug classification
gene* approval
Nitisinone HPD Anti-tyrosinaemia agents 2002 Small molecule
Ezetimibe NPC1L1 Anticholesteraemic agents 2002 Small molecule
Alpha-1 proteinase ELA2 Enzyme replacement agents 2002 Biotechnological; serum protein
inhibitor
Alefacept CD2 Immunosuppressive agents 2003 Biotechnological; fusion protein
Aprepitant TACR1 Anti-emetic agents 2003 Small molecule
Bortezomib PSMB1 Antineoplastic agents 2003 Small molecule
Efalizumab ITGAL Immunomodulatory agents; 2003 Biotechnological; monoclonal antibody
immunosuppressive agents (now withdrawn)
Gefitinib EGFR Antineoplastic agents 2003 Small molecule
Omalizumab IgE Anti-asthmatic agents 2003 Biotechnological; monoclonal antibody
Miglustat UGCG Glycosphingolipid synthesis 2003 Small molecule
inhibitors
Pemetrexed GART Antineoplastic agents 2004 Small molecule
Bevacizumab VEGF Antineoplastic agents 2004 Biotechnological; monoclonal antibody
Cinacalcet CASR Calcimimetic agents 2004 Small molecule
Natalizumab ITGA4 Immunomodulatory agents 2004 Biotechnological; monoclonal antibody
Palifermin FGFR2 Antimucositis agents 2004 Biotechnological; recombinant protein
Dantrolene RYR1 Muscle relaxants 2005 Small molecule
Pramlintide RAMP1 Hypoglycaemic agents 2005 Biotechnological; hormone; synthetic
peptide
Exenatide GLP1R Antidiabetic agents 2005 Biotechnological; hormone; synthetic
peptide
Mecasermin IGF1R Hormone replacement agents 2005 Biotechnological; recombinant protein
Abatacept CD80 Antirheumatic agents 2005 Biotechnological; fusion protein
Sorafenib
RAF1 Antineoplastic agents 2005 Small molecule
Sunitinib FLT1 Antineoplastic agents 2006 Small molecule
Lubiprostone CLCN2 Anticonstipation agents 2006 Small molecule
Dasatinib SRC Antineoplastic agents 2006 Small molecule
Vorinostat HDAC1 Antineoplastic agents 2006 Small molecule
Sitagliptin DPP4 Hypoglycaemic agents 2006 Small molecule
Aliskiren REN Antihypertensive agents 2007 Small molecule
Eculizumab C5 Immunomodulatory agents 2007 Biotechnological; monoclonal antibody
Maraviroc CCR5 Anti-HIV agents; antiviral agents 2007 Small molecule
Rilonacept IL1A Anti-inflammatory agents 2008 Biotechnological; fusion protein
Romiplostim MPL Haematopoiesis-stimulating agents 2008 Biotechnological; fusion protein
Plerixafor CXCR4 Haematopoiesis-mobilizing agents 2008 Small molecule
Canakinumab IL1B Anti-inflammatory agents 2009 Biotechnological; monoclonal antibody
Ustekinumab IL12B Antipsoriatic agents 2009 Biotechnological; monoclonal antibody
Ecallantide KLK1 Treatment for hereditary angioedema 2009 Biotechnological peptide
Tocilizumab IL6R Immunosuppressive agents 2010 Biotechnological; monoclonal antibody
Carglumic acid CPS1 Treatment of hyperammonaemia 2010 Small molecule
Denosumab RANKL Osteoporosis prophylaxis 2010 Biotechnological; monoclonal antibody
Fingolimod S1PR1 Immunosuppressive agents 2010 Small molecule
*See Supplementary information S2 (box) for a list of all gene names. A recombinant form of teriparatide was approved as an osteoporosis therapy in 2002.


Several inhibitors of protein kinases have more than one target that may underlie their therapeutic activity. One of the target genes that provides the basis for
classification of the drug as acting on a previously unexploited target is listed in the table. For a full list of the drugtarget interactions in our data set, please see
Supplementary information S1 (table).

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 585

2011 Macmillan Publishers Limited. All rights reserved

A N A LY S I S
2003) were approved. As noted above, there was a stable
rate of introduction of NTDs that target GPCRs, hydro-
lases, isomerases and oxidoreductases in all three inno-
vation peaks, and ~50% of all of the drugs that have been
approved since 1982 fall into one of these categories.
Closer inspection of the NTDs reveals that small-mol-
ecule drugs were the most common class of agents acting
on novel targets, comprising 60% of all NTDs, but it also
reveals an increase in the development of biotechnology-
based NTDs such as monoclonal antibodies and fusion
proteins during the past two decades (TABLE1). The first
monoclonal antibody drug that was approved for sale
in the United States was muromonabCD3, which is an
immunosuppressant that was approved by the FDA in
1986. Since then, the number of monoclonal antibody
drugs has steadily increased, and they now comprise
a considerable proportion of all NTDs. In the mid- to
late1990s (19942000) monoclonal antibody drugs
comprised 24% of all NTDs, and between 2001 and 2010
they comprised 20% of all NTDs. Monoclonal antibodies
have also been a major commercial success, with sales
rising dramatically in the past decade. For example, the
total market for the four most successful monoclonal
antibodies infliximab (Remicade; Centocor Ortho
Biotech), rituximab (Rituxan; Genentech/Roche/Biogen
Idec), adalimumab (Humira; Abbott) and bevacizumab
(Avastin; Genentech/Roche) increased by a fac-
tor of 3.90 from 2004 to 2010, whereas the total global
drug market during the same period increased by fac-
tor of 1.53, according to data from IMS Health MIDAS
(December 2008, 2009 and 2010).
The majority of drugs (14 out of 15) with the highest
global sales in 2009 were approved by the FDA during
the past 15years, during the second innovation peak,
which is unsurprising as these are the products that still
have patent protection and have also had sufficient time
to become established in the market. A common feature
of all of these drugs is that they target defined protein
structures that are encoded by the human genome. This
is comparable to 65% of drugs in the DrugBank data-
base that target effect-mediating structures encoded
by the human genome. Other target categories include
targets that are produced by pathogens, such as viral
and bacterial proteins, and non-genomic structures
such as extracellular macromolecules and DNA. The
DrugBank database also includes various other agents,
such as osmotic agents, sclerosing agents, nutrient sup-
plements and inactive diagnosticagents.
The most common indication for NTDs is cancer
treatment: ~19% of all NTDs that have been approved
since 1983 are anticancer drugs. Advances in the under-
standing of the molecular basis of cancer during this
period have contributed substantially to this trend, and
have resulted in a shift from traditional cytotoxic thera-
pies to the development of drugs that specifically target
particular proteins that are linked to various cancers,
such as small-molecule kinase inhibitors and monoclo-
nal antibodies that bind to proteins on the surface of
cancer cells. One notable example is the first marketed
small-molecule kinase inhibitor, imatinib (Gleevec;
Novartis), which by inhibiting the mutant BCRABL
586 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc
2011 Macmillan Publishers Limited. All rights reserved
kinase that is present in patients with chronic myeloid
leukaemia dramatically improved disease treatment,
and demonstrated the potential of molecular targets in
anticancer drug discovery, which are now being widely
pursued10.
GPCRs are clearly the most commonly exploited class
of drug targets (FIG.2) approximately 36% of all drugs in
our data set target GPCRs and they also represent the
largest class of target structures for NTDs that have been
approved since 1983; approximately 17% of all targets for
which NTDs have been introduced since 1982 have been
GPCRs. According to data from IMS Health MIDAS, six
out of the 20 drugs (30%) with the highest global sales in
2010 clopidogrel (Plavix; Sanofi/Bristol-Myers Squibb),
quetiapine (Seroquel; AstraZeneca), olanzapine (Zyprexa;
Lilly), montelukast (Singulair; Merck), aripiprazole
(Abilify; Bristol-Myers Squibb) and valsartan (Diovan;
Novartis) target GPCRs. In addition, 63 out of the 200
drugs (~32%) with the highest sales in the United States
in 2009 target GPCRs (see the Drugs.com website). The
majority of pharmacologically exploited GPCRs belong to
the Rhodopsin family (reviewed in REF.11).
Other common receptor target structures for NTDs
in the period that was studied include cytokine receptors,
receptor tyrosine kinases, ligand-gated ion channels and
integrins. Enzymes represent the second largest group
of novel target structures and most commonly belong
to the hydrolase, oxidoreductase or transferase protein
families (EC3, EC1 and EC2, respectively). Novel
hydrolase targets have been dominated by peptidases
and ester hydrolases (EC3.4 and EC3.1). Examples
of such targets include renin, which is a peptidase
that is targeted by the antihypertensive drug aliskiren
(Tekturna/Rasilez; Novartis) (approved in 2007) and
phosphodiesterase 5, which is an ester hydrolase that
is targeted by the erectile dysfunction drug sildenafil
(Viagra; Pfizer) (approved in 1998). Novel targets in
the transferase family have been dominated by phos-
phorous-containing group-transferases (EC2.7) such
as 5-AMP-activated protein kinase, which is indirectly
activated by metformin (approved in 1995). However,
the exact mechanism of activation of 5-AMP-activated
protein kinase by metformin remains to be estab-
lished12. NTDs that modulate oxidoreductases often
target enzymes that act on the CHOH group of donors,
with NAD+ or NADP+ as the acceptor in redox reactions
(EC1.1.1). Some examples include: 3hydroxy3meth-
ylglutaryl-CoA (HMG-CoA) reductase, which is
targeted by the statin class of cardiovascular drugs
to reduce high levels of low-density lipoprotein cho-
lesterol; alcohol dehydrogenase, which is targeted by
disulfiram for the treatment of alcohol dependency; and
inosine 5-monophosphate dehydrogenases, which are
targeted by the immunosuppressive drug mycopheno-
late mofetil (CellCept; Roche).
Drugtarget networks
Protein networks or modules are increasingly being
studied in the field of network biology using methods
from graph theory, which is a growing field within com-
puter science. Much of network biology has focused on
 A N A LY S I S

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Figure 4 | Drugtarget network: summary. This figure provides a graphical representation of all of the interactions
between drugs and therapeutic drug targets in our curated data set. Nodes represent targets (shown as triangles) and
0CVWTG4GXKGYU^&TWI&KUEQXGT[
drugs (shown as circles). Novel target drugs (NTDs) are represented with large circles and drugs with established targets
are represented with small circles. Interacting drugs and targets are connected with lines. This network was created using
Cytoscape. Several isolated components have been identified in our data set, the largest of which we have called the giant
component. The giant component includes 49% of all drugs and 30% of all drug targets in our data set. See Supplementary
information S3 (figure) to view this drugtarget network in greater detail, as well as the labels at full size.

interactions between proteins, which have been called target functional class and novelty (that is, whether the
interactome networks. Drugtarget interactions have drug targeted a previously unexploited target). The net-
also been studied in this context 9. The field of interac- work was viewed in Cytoscape and analysed using local
tomics represents a new way to understand the success Pythonscripts.
of drug targets in the context of their functional milieu. The drugtarget network consists of many subnet-
Topographical analysis of the complex network of inter- works; that is, clusters of connected drug targets. The
cellular protein interactions may also lead to new ave- largest of these components, which we have called the
nues for target prediction13,14. giant component (FIG.4), contains 489 drugs (49% of
We created a drugtarget network from our curated the total) and 131 targets (30% of the total). The giant
data set (which includes 989 drugs and 435 effect-medi- component includes 50% of all drugs from the top 10
ating protein targets) by connecting drugs with their indication classes. The giant component is also biased
known targets (FIGS4,5,6). The drugtarget network was in terms of the type of targets; 42% of all receptor tar-
integrated with annotation concerning drug indication, gets and 66% of all transporter targets are found in the

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 587

2011 Macmillan Publishers Limited. All rights reserved

A N A LY S I S

C %GVWZKOCD D 5KNFGPCN
7FGPCN 8CTFGPCN
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'4$$
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#$.
+OCVKPKD 2&)(4#
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54%
$GECRNGTOKP 1VJGTKPFKECVKQPENCUUGU 'P\[OGU
1VJGTVCTIGVU
0KNQVKPKD #$. &&4
Figure 5 | Drugtarget network: selected networks. Networks of particular interest from the overall network are shown in
0CVWTG4GXKGYU^&TWI&KUEQXGT[
this figure. a | The interaction networks of receptor tyrosine kinase inhibitors for cancer treatment are depicted. These drugs
form two networks that are centred around two receptor tyrosine kinases: the epidermal growth factor receptor (EGFR) and
the platelet-derived growth factor receptor subunits A and B (PDGFRA and PDGFRB). Becaplermin, which is approved for the
topical treatment of foot ulcers in patients with diabetes, is the only agent in these networks that is not an anticancer drug.
However, it has been associated with an increased risk of cancer, and now has a black box warning on its label. b | The
interaction network of phosphodiesterase (PDE) inhibitors is depicted; the indications of drugs in this network encompass the
treatment of asthma and chronic obstructive pulmonary disease (xanthine derivatives theophylline, dyphylline and
enprofylline), erectile dysfunction (vardenafil, sildenafil and tadalafil) and congestive heart failure (amrinone, milrinone and
enoximone). Platelet aggregation inhibitors (cilostazol, dipyridamole and pentoxifylline), the spasmolytic drug papaverine and
the familiar stimulant caffeine are also included in this network. As in Figure 4, nodes represent targets (shown as triangles) and
drugs (shown as circles). Drugs with novel targets are represented with large circles and drugs with established targets are
represented with small circles. Interacting drugs and targets are connected with lines. The original network was created using
Cytoscape. ADA, adenosine deaminase; ADORA1, adenosine receptor A1; CSF1R, macrophagecolony-stimulating factor 1
receptor; DDR1, discoidin domain receptor tyrosine kinase 1; EPHA2, ephrin type A receptor 2; FLT1, fms-like tyrosine kinase 1;
KDR, kinase insert domain receptor; LCK, lymphocyte-specific protein tyrosine kinase; NTRK1, neurotrophic tyrosine kinase
receptor type 1; STAT5B, signal transducer and activator of transcription 5; YES1, Yamaguchi sarcoma viral oncogene homolog 1.

giant component, whereas only 5% of enzyme targets
and 6% of miscellaneous targets are found here. Overall,
58% of the targets in the giant component are receptors
and all but one of these are GPCRs or ligand-gated ion
channels two very traditional classes of pharmaco-
logical targets. The drugs in the giant component have a
significantly higher number of target interactions than
drugs in the smaller components (P<0.001; Wilcoxon
signed-rank test). Drugs in the giant component have an
average of three targets, whereas drugs outside the giant
component have an average of 1.5 targets.
Targets within the giant component have a much
longer history than the network as a whole, consider-
ing the FDA approval dates of drugs within this compo-
nent. The drugs in the giant component have a median
approval year before 1982, which is the cut-off date for
drug approvals in our data set. Out of all of the drugs
that were approved after 1982 in the giant component,
only 12 are NTDs. Hence, it is clear that almost half of all
drugs on the market which represent the indication
classes in which a large research effort has been made
share a similar target interaction profile and exploit a
limited part of the proteome. In addition, the main inno-
vations within this cluster of successful drugs occurred
before the one drug, one target focus of recent times.
The success of some of the drugs in the giant component
could be due to the fact that they utilize multiple targets.
This highlights the importance of polypharmacology
and an understanding of the target profile in relation to
the interactome for the discovery of newdrugs.
Discussion
In this analysis, we observed an approximately steady
rate of introduction of new drugs targeting molecules
encoded by the human genome, and an approxi-
mately steady rate of introduction of NTDs into the US

588 | AUGUST 2011 | VOLUME 10 www.nature.com/reviews/drugdisc

2011 Macmillan Publishers Limited. All rights reserved

 A N A LY S I S

assessed by the rate of introduction of new drugs and

NTDs does not appear to have decreased substan-
4KNQPCEGRV %CPCMKPWOCD +.$ %& 'NVTQODQRCI 'EWNK\WOCD tially in the period we studied, given the considerable
increase in investment in research and development by
the pharmaceutical industry during this period15,16, the
+.# +.$ 7UVGMKPWOCD #DCVCEGRV /2. % lack of an increase in the rate of innovation could be
considered as alarming.
Our analysis also highlights that the majority of
new drugs that were approved during this period target
%& 4QOKRNQUVKO previously exploited structures that are encoded by the
human genome. Our estimate for the number of current
drug targets encoded by the human genome is somewhat
/CTCXKTQE 2NGTKZCHQT 'ZGPCVKFG 5CZCINKRVKP &CPVTQNGPG 'ECNNCPVKFG higher than some previous estimates35, as we have not
filtered our data set with regard to gene family redun-
dancies or rule-of-five compliant molecules but instead
focused on individual genes (that is, single positions on
%%4 %:%4 ).24 &22 4;4 -.- the genome).
Our analysis of drugtarget connections reveals a
bias (FIGS4,5,6). As older drugs have been more thor-
4#/2 .KTCINWVKFG 5KVCINKRVKP oughly studied and a higher number of drugprotein
interactions have been documented for these drugs, they
have higher connectivity in the drugtarget network.
6JGTCRGWVKECEVKQPU 6CTIGVENCUU
Newer NTDs, by definition, tend to be disconnected
2TCONKPVKFG 4#/2
#PVKKPCOOCVQTKGU 4GEGRVQTU from the giant component of the network, and this is
1VJGTKPFKECVKQPENCUUGU 'P\[OGU seen with NTDs that were introduced into the market
6TCPURQTVGTU from 2005 to 2010 (FIG.6). Apart from receptor tyrosine
1VJGTVCTIGVU kinase inhibitors and monoclonal antibodies for cancer
4#/2 therapy, which show some degree of interconnectivity by
Figure 6 | Isolated smaller networks of drugs with novel targets that were forming a separate subnetwork (FIG.5), NTDs that were
0CVWTG4GXKGYU^&TWI&KUEQXGT[
approved between 2005 and 2010, and their corresponding target-encoding introduced from 2005 to 2010 are all disconnected from
genes. These smaller networks are of particular interest as they not only represent novel the giant component, and instead form small isolated
drug targets but also represent novel molecular mechanisms for treatment. Several networks consisting of two or three nodes. These smaller
drugs are included in this panel. These include maraviroc, which inhibits the entry of the networks are, however, of particular interest as they not
human immunodeficiency virus into human cells by blocking CC chemokine receptor only represent novel drug targets but also often repre-
type 5 (CCR5) on human lymphocytes. The following antidiabetic drugs are also sent novel molecular mechanisms for treatment. Some
included: sitagliptin, which was the first dipeptidyl peptidase 4 (DPP4) inhibitor; examples are given in FIG.6. Overall, this stresses the
pramlintide, which is an amylin analogue that interacts with the protein complexes
complexity of the automatic use of general drugtarget
receptor activity-modifying protein 1 (RAMP1), RAMP2 and RAMP3; and exenatide,
which is an analogue of a peptide contained in the venom of the Gila monster connectivity network analysis, and highlights the impor-
(Heloderma suspectum) and was the first drug to target glucagon-like peptide 1 receptor tance of the specification of the unique non-redundant
(GLP1R). The panel also includes the haematopoiesis-stimulating drugs plerixafor, which drug targets, including the distinction between new and
interacts with CXC chemokine receptor type 4 (CXCR4), and romiplostim, which was the old drugtargets.
first drug to interact with the thrombopoietin receptor (MPL). Other drugs in this panel The idea of a unique point of pharmacological inter-
include the muscle relaxant dantrolene, which was the first drug to act on ryanodine vention for each disease one drug/disease, one target
receptor 1 (RYR1), and ecallantide, which inhibits the protein kallikrein 1 (KLK1) and is has validity in reducing side effects for the treatment
indicated for the treatment of hereditary angioedema. This panel also includes the fusion of several diseases. However, rigid application of this the-
proteins rilonacept, which targets interleukin1 (IL1), and abatacept, which targets T ory in drug discovery may inadvertently exclude possible
lymphocyte activation antigen CD80 and T lymphocyte activation antigen CD86. The
leads. In the case of antipsychotic drugs for example, for
monoclonal antibodies canakinumab (which targets IL1), ustekinumab (which targets
the p40 subunit of IL12 and IL23) and eculizumab (which was the first drug to target which the dopamine D2 receptor has been theoretically
complement protein C5) are also included; these monoclonal antibodies are indicated suggested as the intended target, drug target promiscu-
for the treatment of various immunoinflammatory diseases. As in Figure 4, drugs with ity has instead been seen to have more beneficial effects
novel targets (NTDs) are represented with large circles and drugs with established than selective dopamine D2 receptor ligands. In the case
targets are represented with small circles. Interacting drugs and targets are connected of anticancer drugs, however, the focus on selectivity
with lines. The original network was created using Cytoscape. has generated major treatment benefits, as illustrated
by the previously mentioned example of imatinib and
other kinase inhibitors, although even in these cases it
market from 1982 to 2010. Three innovation peaks should be noted that these compounds often potently
were observed in the rate of introduction of NTDs; the inhibit several kinases. The introduction of monoclonal
potential factors underlying these peaks are multiple antibodies as a therapeutic modality has had a major
and diverse, ranging from scientific and technological medical impact (particularly in the past decade), as it
advances to changes in regulatory policy, and are not enables rational target selection and high target specific-
discussedhere. Although the rate of innovation as ity. There has been, and continues to be, great interest in

NATURE REVIEWS | DRUG DISCOVERY VOLUME 10 | AUGUST 2011 | 589

2011 Macmillan Publishers Limited. All rights reserved

A N A LY S I S

the development of new antibodies within fields such
as cancer and inflammation, in which the drug target
is often expressed at higher levels in the diseasestate.
These new opportunities highlight the need to gain
a deeper understanding of disease processes at the
molecular level for a wider range of targets, as noted in
an early paper on drug targets17. In recent years, a range
of new candidate targets have been identified from
genome-wide association studies for several common
complex disorders such as obesity, diabetes, cancer and
cardiovascular disease. New technologies such as next-
generation sequencing will allow these types of studies
to be performed on an even larger scale and in closer
association with detailed clinical phenotyping, which
could help to validate the therapeutic relevance of such
targets, which arguably remains one of the crucial chal-
lenges in drug discovery research. Simultaneous exploi-
tation of several targets for disease treatment also poses
a major challenge owing to the complexity of cellular
signalling and drugprotein interactions in the human
body. The burgeoning concept of network pharma-
cology aims to quantify these interactions and could
provide a general tool for identifying new targets for
rational drug discovery.

1. Goodman, L.S., Gilman, A., Hardman, J.G., Gilman,
A.G. & Limbird, L.E. Goodman & Gilmans The
Pharmacological Basis of Therapeutics 9th edn
(McGraw-Hill, New York,1996).
2. Drews, J. Genomic sciences and the medicine of
tomorrow. Nature Biotech. 14, 15161518
(1996).
3. Hopkins, A.L. & Groom, C.R. The druggable genome.
Nature Rev. Drug Discov. 1, 727730 (2002).
4. Imming, P., Sinning, C. & Meyer, A. Drugs, their
targets and the nature and number of drug targets.
Nature Rev. Drug Discov. 5, 821834 (2006).
5. Overington, J.P., Al-Lazikani, B. & Hopkins, A.L. How
many drug targets are there? Nature Rev. Drug
Discov. 5, 993996 (2006).
6. Wishart, D.S. etal. DrugBank: a knowledgebase for
drugs, drug actions and drug targets. Nucleic Acids
Res. 36, D901D906 (2008).
7. Wishart, D.S. etal. DrugBank: a comprehensive
resource for insilico drug discovery and exploration.
Nucleic Acids Res. 34, D668D672 (2006).
8. Knox, C. etal. DrugBank 3.0: a comprehensive
resource for omics research on drugs. Nucleic Acids
Res. 39, D1035D1041 (2011).
This paper describes the most recent version of the
DrugBank database, which is one of the most
important sources of information on drugs and drug
targets.
9. Yildirim, M.A., Goh, K.I., Cusick, M.E., Barabasi,
A.L. & Vidal, M. Drugtarget network. Nature
Biotech. 25, 11191126 (2007).
This was one of the first papers to present a
functional view on drugtarget interactions by
illustrating them as networks. This paper also
integrates and analyses drug targets in the context
of disease genetics and proteinprotein
interactomics.
10. Stegmeier, F., Warmuth, M., Sellers, W.R. & Dorsch, M.
Targeted cancer therapies in the twenty-first century:
lessons from imatinib. Clin. Pharmacol. Ther. 87,
543552 (2010).
11. Lagerstrom, M.C. & Schioth, H.B. Structural diversity
of G protein-coupled receptors and significance for
drug discovery. Nature Rev. Drug Discov. 7, 339357
(2008).
12. Hardie, D.G. Role of AMP-activated protein kinase in
the metabolic syndrome and in heart disease. FEBS
Lett. 582, 8189 (2008).
13. Zhu, M. etal. The analysis of the drugtargets based
on the topological properties in the human protein
protein interaction network. J.Drug Target. 17,
524532 (2009).
This paper uses topological methodology to
analyse the properties of drug targets in the
context of proteinprotein interaction networks.
This information is then used for target prediction.
14. Hopkins, A.L. Network pharmacology: the next
paradigm in drug discovery. Nature Chem. Biol. 4,
682690 (2008).
15. Paul, S.M. etal. How to improve R&D productivity:
the pharmaceutical industrys grand challenge. Nature
Rev. Drug Discov. 9, 203214 (2010).
16. Kaitin, K.I. Deconstructing the drug development
process: the new face of innovation. Clin. Pharmacol.
Ther. 87, 356361 (2010).
17. Drews, J. Drug discovery: a historical perspective.
Science 287, 19601964 (2000).
Acknowledgements
The authors would like to thank J. Weigelt, Karolinska
Institute, Stockholm, for providing valuable comments on an
early version of the manuscript. These studies were sup-
ported by the Swedish Research Council, the Novo Nordisk
Foundation and the Swedish Brain Research Foundation.
Competing interests statement
The authors declare no competing financial interests.
FURTHER INFORMATION
Drugs@FDA website: http://www.accessdata.fda.gov/
scripts/cder/drugsatfda/
DrugBank database website: http://www.drugbank.ca
Drugs.com website: http://www.drugs.com
FDA Orange book: http://www.accessdata.fda.gov/scripts/
cder/ob/default.cfm
IMS Health: http://www.imshealth.com
SUPPLEMENTARY INFORMATION
See online article: S1 (table) | S2 (box) | S3 (figure)
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