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Table 1a | Enzymes
Type Activity of drug Drug examples
Oxidoreductases
Aldehyde dehydrogenase Inhibitor Disulfiram39
Monoamine oxidases (MAOs) MAO-A inhibitor Tranylcypromine40, moclobemide41
MAO-B inhibitor Tranylcypromine40
Cyclooxygenases (COXs) COX1 inhibitor Acetylsalicylic acid, profens, acetaminophen and
dipyrone (as arachidonylamides)42,43
COX2 inhibitor Acetylsalicylic acid, profens, acetaminophen and
dipyrone (as arachidonylamides)44
Vitamin K epoxide reductase Inhibitor Warfarin, phenprocoumon45
Aromatase Inhibitor Exemestane46
Lanosterol demethylase (fungal) Inhibitor Azole antifungals47
Lipoxygenases Inhibitor Mesalazine48
5-lipoxygenase inhibitor Zileuton49
Thyroidal peroxidase Inhibitor Thiouracils50
Iodothyronine-5 deiodinase Inhibitor Propylthiouracil50
Inosine monophosphate dehydrogenase Inhibitor Mycophenolate mofetil51
HMG-CoA reductase Inhibitor Statins52
5-Testosterone reductase Inhibitor Finasteride, dutasteride53
Dihydrofolate reductase (bacterial) Inhibitor Trimethoprim54
Dihydrofolate reductase (human) Inhibitor Methotrexate, pemetrexed55
Dihydrofolate reductase (parasitic) Inhibitor Proguanil56
Dihydroorotate reductase Inhibitor Leflunomide57
Enoyl reductase (mycobacterial) Inhibitor Isoniazid58
Squalene epoxidase (fungal) Inhibitor Terbinafin59
14 reductase (fungal) Inhibitor Amorolfin60
Xanthine oxidase Inhibitor Allopurinol61
4-Hydroxyphenylpyruvate dioxygenase Inhibitor Nitisinone62
Ribonucleoside diphosphate reductase Inhibitor Hydroxycarbamide63
Transferases
Protein kinase C Inhibitor Miltefosine64,65
Bacterial peptidyl transferase Inhibitor Chloramphenicol67
Catecholamine-O-methyltransferase Inhibitor Entacapone68
RNA polymerase (bacterial) Inhibitor Ansamycins69
Reverse transcriptases (viral) Competitive inhibitors Zidovudine70,71
Allosteric inhibitors Efavirenz72,73
DNA polymerases Inhibitor Acyclovir, suramin74,75
GABA transaminase Inhibitor Valproic acid76, vigabatrin77
Tyrosine kinases PDGFR/ABL/KIT inhibitor Imatinib78
EGFR inhibitor Erlotinib79
VEGFR2/PDGFR/KIT/FLT3 Sunitinib66
VEGFR2/PDGFR/RAF Sorafenib109
Glycinamide ribonucleotide formyl transferase Inhibitor Pemetrexed55
Phosphoenolpyruvate transferase (MurA, bacterial) Inhibitor Fosfomycin80,81
Human cytosolic branched-chain aminotransferase Inhibitor Gabapentin82
(hBCATc)
EGFR, epidermal growth factor receptor; GABA, -amino butyric acid; HMG-CoA, 3-hydroxy-3-methyl-glutaryl coenzyme A; PDGFR, platelet-derived growth factor receptor;
VEGFR, vascular endothelial growth factor receptor.
Table 1b | Enzymes
Type Activity of drug Drug examples
Hydrolases (proteases)
Aspartyl proteases (viral) HIV protease inhibitor Saquinavir, indinavir94
Hydrolases (serine proteases)
Unspecific Unspecific inhibitors Aprotinine95
Bacterial serine protease Direct inhibitor -lactams96
Bacterial serine protease Indirect inhibitor Glycopeptides97
Bacterial lactamases Direct inhibitor Sulbactam98
Human antithrombin Activator Heparins99-101
Human plasminogen Activator Streptokinase102,103
Human coagulation factor Activator Factor IX complex, Factor VIII104
Human factor Xa Inhibitor Fondaparinux105
Hydrolases (metalloproteases)
Human ACE Inhibitor Captopril106
Human HRD Inhibitor Cilastatin107
Human carboxypeptidase A (Zn) Inhibitor Penicillamine108
Human enkephalinase Inhibitor Racecadotril110
Hydrolases (other)
26S proteasome Inhibitor Bortezomib83
Esterases AChE inhibitor Physostigmine84
AChE reactivators Obidoxime85
PDE inhibitor Caffeine86
PDE3 inhibitor Amrinon, milrinone87
PDE4 inhibitor Papaverine88
PDE5 inhibitor Sildenafil89
HDAC inhibitor Valproic acid76
HDAC3/HDAC7 inhibitor Carbamezepine90
Glycosidases (viral) -glycosidase inhibitor Zanamivir, oseltamivir91
Glycosidases (human) -glycosidase inhibitor Acarbose92
Lipases Gastrointestinal lipases inhibitor Orlistat93
Phosphatases Calcineurin inhibitor Cyclosporin111
Inositol polyphosphate phosphatase inhibitor Lithium ions112,113
GTPases Rac1 inhibitor 6-Thio-GTP (azathioprine metabolite)114
Phosphorylases Bacterial C55-lipid phosphate dephosphorylase inhibitor Bacitracin115
Lyases
DOPA decarboxylase Inhibitor Carbidopa116
Carbonic anhydrase Inhibitor Acetazolamide117
Histidine decarboxylase Inhibitor Tritoqualine118
Ornithine decarboxylase Inhibitor Eflornithine119
Soluble guanylyl cyclase Activator Nitric acid esters, molsidomine120-123
Isomerases
Alanine racemase Inhibitor d-Cycloserine124
DNA gyrases (bacterial) Inhibitor Fluoroquinolones125
Topoisomerases Topoisomerase I inhibitor Irinotecan126
Topoisomerase II inhibitor Etoposide127
8,7 isomerase (fungal) Inhibitor Amorolfin128
Ligases (also known as synthases)
Dihydropteroate synthase Inhibitor Sulphonamides129
Thymidylate synthase (fungal and human) Inhibitor Fluorouracil130
Thymidylate synthase (human) Inhibitor Methotrexate, pemetrexed55,131
Phosphofructokinase Inhibitor Antimony compounds132
mTOR Inhibitor Rapamycin133
Haem polymerase (Plasmodium) Inhibitor Quinoline antimalarials134
1,3--d-glucansynthase (fungi) Inhibitor Caspofungin135
Glucosylceramide synthase Inhibitor Miglustat136
ACE, angiotensin-converting enzyme; AChE, acetylcholinesterase; HDAC, histone deacetylase; HRD, human renal dehydropeptidase; mTOR, mammalian target of rapamycin;
PDE, phosphodiesterase.
Table 2 | Substrates, metabolites and proteins Only this will give a net clinical effect that
might be considered beneficial. As yet, we
Substrate Drug substance are unable to count targets in this sense
Asparagine Asparaginase137 (macro-targets), and it is only by chance
Urate Rasburicase (a urate oxidase)138 that most of the current in vitro screening
techniques will identify drugs that work
VAMPsynaptobrevin, SNAP25, Syntaxin Light chain of the botulinum neurotoxin
(Zn-endopeptidase)139 through such targets.
Greater knowledge of how drugs
SNAP, synaptosomal-associated protein; VAMP, vesicle-associated membrane protein.
interact with the body (mechanisms of
action, drugtarget interactions) has led
that tries to cover all drug substances. administration of cocaine, followed by a to a reduction of established drug doses
For the present purpose, we chose to limit gradual increase in steady-state dopamine and inspired the development of newer,
our analysis to published consensus data concentration8. Indeed, the dynamics of the highly specific drug substances with a
on one to three of the main biochemical response are what really matters, but are known mechanism of action. However,
targets of drug substances. If there was difficult to assess experimentally. Further a preoccupation with the molecular details
no consensus or proof of target and/or examples of dynamic (process) mechanisms has sometimes resulted in a tendency to
targeteffect connection, we included the of drug action include non-covalent modi- focus only on this one aspect of the drug
respective substances in a part of our list fications of the active centre (for example, effects. For example, cumulative evidence
called Unknown mechanism of action. acetylation of bacterial transpeptidases by now suggests that the proven influence of
-lactam antibiotics); allosteric modulation certain psychopharmaceuticals on neuro-
The dynamics of drug effects. It would (for example, benzodiazepine modulation transmitter metabolism has little to do
ultimately be desirable to move away from a of GABA (-amino butyric acid) receptors); with the treatment of schizophrenia or
static target definition, but this is hindered drugs that require the receptor to be in a the effectiveness of the drug for this
mainly by our inability to gauge the inter- certain state for binding and inhibition indication10. Here, we touch on a very
action of the aforementioned ripples in (for example, trapping of K+ channels by basic and important point that cannot be
other words, the actual pharmacodynamics methanesulphoanilide anti-arrhythmic expanded in the context of this paper but
of drugs. All drugs somehow interfere with agents9); drugs that exert their effect indi- which deserves to be stressed: with all our
signal transduction, receptor signalling and rectly and require a functional background efforts to understand the molecular basis of
biochemical equilibria. For many drugs (for example, the catechol-O-methyl drug action, we must not fall into the trap
we know, and for most we suspect, that transferase inhibitor entacapone, the effect of reductionism. As Roald Hoffmann aptly
they interact with more than one target. of which is due to the accumulation of non- said in his speech at the Nobel Banquet:
So, there will be simultaneous changes in metabolized dopamine); anti-infectives
several biochemical signals, and there will that require the target organism to be Chemistry reduced to its simplest terms,
be feedback reactions of the pathways dis- in an active, growing state (for example is not physics. Medicine is not chemistry ....
turbed. In most cases, the net result will not -lactams); molecules requiring activation knowledge of the specific physiological and
be linearly deducible from single effects. (prodrugs, such as paracetamol); and cases eventually molecular sequence of events
For drug combinations, this is even more of modifications of a substrate or cofactor does not help us understand what [a] poet
complicated. A mechanism-based simula- (for example, asparaginase, which depletes has to say to us.
tion of pharmacodynamic drugdrug tumour cells of asparagine; isoniazide,
interactions was published recently6, which is activated by mycobacteria leading With diseases such as type 1 diabetes, for
highlighting the complexity of interaction to an inactive covalently modified NADH; example, the molecule insulin is indeed all
analyses for biological systems. Awareness and vancomycin, which binds to the that is needed to produce a cure, although
is also increasing of the nonlinear correla- building block bacteria use for constructing we cannot imitate its regulated secre-
tion of molecular interactions and clinical their cell wall). tion. With diseases such as psychoses, for
effects. For example, the importance of example, antipsychotic drugs might not
receptorreceptor interactions (receptor The macro- and micro-world of targets. correct nor even interfere with the aspect
mosaics) was recently summarized for So, for estimations of the total number of of the human constitution that is actually
GPCRs, resulting in the hypothesis that targets, a clinically relevant target might deranged, and with such drugs molecular
cooperativity is important for the decoding consist not of a single biochemical entity, but determinism might be counterproductive
of signals, including drug signals7. Another the simultaneous interference of a number to the use and development of therapeutic
paper reported dopamine fluctuations after of receptors (pathways, enzymes and so on). approaches. It is thought that rather
than chemically providing a cure, these
drugs make the patient more responsive
Box 1 | Drugs with unknown mechanism of action
to a therapy that acts at a different level.
4-Aminosalicylic acid | Alendronate | Ambroxol | Arsenic trioxide | Becaplermin | Bexarotene | Reflections on molecular targets are very
Chloral hydrate | Clofazimine | Dactinomycin (RNA synthesis inhibitor) | Dapsone (folic acid important because drugs are molecules,
synthesis inhibitor) | Diethyl carbamazine | Diethyl ether | Diloxanide | Dinitric oxide | Ethambutol | but it is important not to be too simplistic.
Gentian violet | Ginkgolides | Griseofulvin | Halofantrine | Halothane | Hydrazinophthalazine | Returning to the key question, what do
Limefantrine (antimalarial; prevents haem polymerization) | Levetiracetam | Mebendazole |
we count as a target? In the search for molec-
Methyl-(5-amino-4-oxopentanoate) | Niclosamide | Pentamidine | Podophyllotoxin | Procarbazine |
Selenium sulphide
ular reaction partners of drug substances,
we will have to be content with losing sight
Box 2 | One drug many targets At present, the most commonly used
classification system for drug substances is
Over the past 20 years, drug approval authorities and many pharmacologists have moved away the ATC system16 (see WHO Collaborating
from combination therapies and asked for rational, single-drug, single-target therapies. This is Centre for Drug Statistics Methodology,
understandable, as it rapidly becomes challenging to analyse the contributions of multiple drugs
Further information). It categorizes drug
or those that hit multiple targets to the observed effects, both desirable and undesirable.
The principle that blocking a single pharmacological target with high potency is desirable
substances at different levels: anatomy,
because it minimizes the side effects that come with non-specific drugs has become well- therapeutic properties and chemical proper-
established, almost dogma, in drug development circles. However, a few examples will suffice to ties. We recently proposed an alternative
show that it is an oversimplification. First, despite the appeal of a single-drug-target strategy for classification system17, although we did not
drug development, the most effective anti-arrhythmic compound, amiodarone, is the dirtiest of follow it fully in the arrangement of entries
all anti-arrhythmics33. Second, the problems with highly selective cyclooxygenase-2-inhibitors are in TABLES 18, BOX 1, as explained below.
considered to be due to their very selectivity, which seems to tip the balance of pro- and anti-
thrombotic mediators in an unfavourable way34. Third, propranolol is the first and classic Classification of drug substances according
-sympatholytic agent, but it has neither an absolute selectivity for an adrenoceptor subtype nor to targets. In TABLES 18, we arranged drug
does it address receptors exclusively; for example, it also inhibits phosphatidic acid
substances according to their mechanism
phosphorylase. It is not clear whether the latter activity contributes to the net clinical effects
(hypotension and so on)35. Fourth, oestrogens not only have an intracellular nuclear receptor,
of action. Although the term mechanism of
but also activate a membrane-bound one as well (GPR30)36. The effects of oestrogen result from action itself implies a classification
the interplay of the two mechanisms. Fifth, for papaverine, a smooth-muscle relaxant agent, according to the dynamics of drug sub-
the following activities were recorded, and all seem to be important for the net effect: cyclic stance effects at the molecular level, the
nucleotide phosphodiesterase inhibition, Ca2+-channel blockade and -adrenoreceptor dynamics of these interactions are only
antagonism37. And last, the anticancer drug imatinib was originally moved into clinical speculative models at present, and so
development on the basis of its capacity to inhibit a single target: the BCRABL kinase. It has since mechanism of action can currently only be
become clear that its success could be linked to interaction with at least two other targets; used to describe static (micro)targets, as
indeed, two anticancer drugs, sorafenib and sunitinib, that were developed to inhibit multiple discussed above.
kinases have recently been approved. As with antipyschotics30, such dirty or promiscuous
The actual depth of detail used to define
anticancer drugs might be increasingly sought in the near future38.
the target is primarily dependent on the
amount of knowledge available about the
of some of the net biochemical and espe- nine-teenth century until the 1970s, target and its interactions with a drug.
cially clinical effects of the drugs action. A drug substances were classified in the If the target structure has already been
target definition derived from the net effect same way as other chemical entities: determined, it could still be that the
rather than the direct chemical interaction by the nature of their primary elements, molecular effect of the drug cannot be fully
will require input from systems biology, a functional moieties or organic substance described by the interactions with one
nascent research field that promises to sig- class. Recently, the idea of classifying target protein alone. For example, anti-
nificantly affect the drug discovery process11. drug substances strictly according to their bacterial oxazolidinones interact with
At the other end of the scale of precision, we chemical constitution or structure has 23S-rRNA, tRNA and two polypeptides,
can define some targets very precisely on the been revived. Numerous databases now ultimately leading to inhibition of protein
molecular level: for example, we can say that attempt to gather and organize information synthesis. In this case, a description of the
dihydropyridines block the CaV1.2a splic- on existing or potential drug substances mechanism of action that only includes
ing variant in heart muscle cells of L-type according to their chemical structure interactions with the 23S-rRNA target would
high-voltage activated calcium channels. and diversity. The objective is to create be too narrowly defined. In particular, in
This is an example of a micro-target. It does substance libraries that contain pertinent situations in which the dynamic actions of
make sense to define it because a subtype or information about possible ligands for the drug substance stimulate, or inhibit, a
even splicing variant selectivity could alter new targets (for example, an enzyme or biological process, it is necessary to move
the effectiveness of calcium channel block- receptor) of clinical interest12,13 and, away from the descriptions of single pro-
ers. We could further differentiate between more importantly, to understand the teins, receptors and so on and to view the
genetic, transcriptional, post-transcriptional systematics of molecular recognition14,15 entire signal chain as the target. Indeed,
or age differences between individuals, and (ligandreceptor). it has been pointed out by Swinney in an
again this will make sense in some cases. article on this topic that two components
But for a target count, a line needs to be are important to the mechanism of action ...
drawn somewhere, otherwise the number of In situations in which The first component is the initial mass-
individual patients that receive a drug could action-dependent interaction ... The second
be counted and equated with the number of the dynamic actions of the component requires a coupled biochemi-
known targets. In summary, we will count drug substance stimulate, or cal event to create a transition away from
neither macro- nor micro-targets, but some- inhibit, a biological process, mass-action equilibrium and drug mecha-
thing in between admittedly a somewhat nisms that create transitions to a non-
arbitrary distinction. it is necessary to move away equilibrium state will be more efficient18.
from the descriptions of single This consideration again stresses that dynam-
Classification of current drugs proteins, receptors and so on ics are essential for effective drug action and,
There are a number of possible ways to as discussed above, indicates that an effective
classify drug substances (active pharma- and to view the entire signal drug target comprises a biochemical system
ceutical ingredients). From the end of the chain as the target. rather than a single molecule.
Table 3a | Receptors
Type Activity of drug Drug examples
Direct ligand-gated ion channel receptors
GABAA receptors Barbiturate binding site agonists Barbiturate140
Benzodiazepine binding site agonists Benzodiazepines141
Benzodiazepine binding site antagonists Flumazenil142
Acetylcholine receptors Nicotinic receptor agonists Pyrantel (of Angiostrongylus), levamisole143,144
Nicotinic receptor stabilizing antagonists Alcuronium145
Nicotinic receptor depolarizing antagonists Suxamethonium146
Nicotinic receptor allosteric modulators Galantamine147
Glutamate receptors (ionotropic) NMDA subtype antagonists Memantine148
NMDA subtype expression modulators Acamprosate149
NMDA subtype phencyclidine binding site Ketamine150
antagonists
G-protein-coupled receptors
Acetylcholine receptors Muscarinic receptor agonists Pilocarpine151
Muscarinic receptor antagonists Tropane derivatives152,153
Muscarinic receptor M3 antagonists Darifenacine154
Adenosine receptors Agonists Adenosine155
Adenosine A1 receptor agonists Lignans from valerian156
Adenosine A1 receptor antagonists Caffeine, theophylline
Adenosine A2A receptor antagonists Caffeine, theophylline157
158,159
Adrenoceptors Agonists Adrenaline, noradrenaline, ephedrine
1- and 2-receptors agonists Xylometazoline
1-receptor antagonists Ergotamine160
2-receptor, central agonists Methyldopa (as methylnoradrenaline)
-adrenoceptor antagonists Isoprenaline
1-receptor antagonists Propranolol, atenolol
2-receptor agonists Salbutamol
2-receptor antagonists Propranolol
Angiotensin receptors AT1-receptors antagonists Sartans161
Calcium-sensing receptor Agonists Strontium ions162
Allosteric activators Cinacalcet163
Cannabinoid receptors CB1- and CB2-receptors agonists Dronabinol164
Cysteinyl-leukotriene receptors Antagonists Montelukast165
166
Dopamine receptors Dopamine receptor subtype direct agonists Dopamine, levodopa
D2, D3 and D4 agonists Apomorphine
D2, D3 and D4 antagonists Chlorpromazine, fluphenazine, haloperidol,
metoclopramide, ziprasidone
Endothelin receptors (ETA, ETB) Antagonists Bosentan167
GABAB receptors Agonists Baclofen168
Glucagon receptors Agonists Glucagon169
Glucagon-like peptide-1 receptor Agonists Exenatide170
Histamine receptors H1-antagonists Diphenhydramine171
H2-antagonists Cimetidine172
Opioid receptors 173,174
-opioid agonists Morphine, buprenorphine
-, - and -opioid antagonists Naltrexone
-opioid antagonists Buprenorphine
Neurokinin receptors NK1 receptor antagonists Aprepitant175
GABA, -amino butyric acid; NMDA, N-methyl-d-aspartate.
Table 3b | Receptors
Type Activity of drug Drug examples
Prostanoid receptors Agonists Misoprostol, sulprostone, iloprost176
Prostamide receptors Agonists Bimatoprost177
Purinergic receptors P2Y12 antagonists Clopidogrel178
Serotonin receptors Subtype-specific (partial) agonists Ergometrine, ergotamine160
5-HT1A partial agonists Buspirone179
5-HT1B/1D agonists Triptans180
5-HT2A antagonists Quetiapine, ziprasidone181
5-HT3antagonists Granisetron182
5-HT4 partial agonists Tegaserode183
Vasopressin receptors184 Agonists Vasopressin
V1 agonists Terlipressin185
V2 agonists Desmopressin
OT agonists Oxytocin
OT antagonists Atosiban
Cytokine receptors
Class I cytokine receptors Growth hormone receptor antagonists Pegvisomant186
Erythropoietin receptor agonists Erythropoietin187
Granulocyte colony stimulating factor agonists Filgrastim188
Granulocyte-macrophage colony stimulating factor Molgramostim189
agonists
Interleukin-1 receptor antagonists Anakinra190
Interleukin-2 receptor agonists Aldesleukin191
TNF receptors Mimetics (soluble) Etanercept192
Integrin receptors
Glycoprotein IIb/IIIa receptor Antagonists Tirofiban193
Receptors associated with a tyrosine kinase
Insulin receptor Direct agonists Insulin194
Insulin receptor Sensitizers Biguanides195
Nuclear receptors (steroid hormone receptors)
Mineralocorticoid receptor196 Agonists Aldosterone
Antagonists Spironolactone
Glucocorticoid receptor Agonists Glucocorticoids197
Progesterone receptor Agonists Gestagens198
199
Oestrogen receptor Agonists Oestrogens
(Partial) antagonists Clomifene
Antagonists Fulvestrant
Modulators Tamoxifen, raloxifene200
201,202
Androgen receptor Agonists Testosterone203
Antagonists Cyproterone acetate204
Vitamin D receptor205,206 Agonists Retinoids207
ACTH receptor agonists Agonists Tetracosactide (also known as cosyntropin) 208
Nuclear receptors (other)
Retinoic acid receptors RAR agonists Isotretinoin209
RAR agonists Adapalene, isotretinoin210
RAR agonists Adapalene, isotretinoin210
Peroxisome proliferator-activated PPAR agonists Fibrates211,212
receptor (PPAR)
PPAR agonists Glitazones213
Thyroid hormone receptors Agonists l-Thyroxine214
ACTH, adrenocorticotropic hormone.
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Drugs, their targets and the nature and number of drug targets
Peter Imming, Christian Sinning and Achim Meyer
Nature Reviews Drug Discovery 5, 821834 (2006); doi:10.1038/nrd2132
In Table 3b (page 827), ACTH receptor agonists were wrongly included with nuclear receptors (steroid hormone receptors). They
should have been included with G-protein-coupled receptors in Table 3a (page 826). In Table 3b, the entry in the Vitamin D
receptor row, in the column Drug examples, should be Vitamin D and analogues, not Retinoids, and reference 207 needs to be
deleted accordingly. The authors thank a colleague for drawing their attention to this.