PERSPECTIVES
and to treating targets as static objects. OPINION In the case of G-protein-coupled receptors (GPCRs), the pharmaceutically most useful Drugs, their targets and the nature class of receptors, a re-organization of the protein after drug binding was derived from biochemical data4, but such approaches are and number of drug targets still in their infancy. For most drugs, several if not many targets Peter Imming, Christian Sinning and Achim Meyer were identified. Consequently, we had to decide for every drug substance or drug Abstract | What is a drug target? And how many such targets are there? Here, we class which target(s) to include in our list. consider the nature of drug targets, and by classifying known drug substances on For this, we relied on the existence of lit- the basis of the discussed principles we provide an estimation of the total number erature data that showed some connection of current drug targets. between the interaction of the drug with the biochemical structure of the target and the clinical effect(s) (not side effects). Estimations of the total number of drug • Enzymes (TABLE 1) A chemical with a certain reactivity or targets are presently dominated by analyses • Substrates, metabolites and proteins binding property is used as a drug because of the human genome, which are limited (TABLE 2) of its clinical effects, but it should be for various reasons, including the inability • Receptors (TABLE 3) stressed that it can be challenging to prove to infer the existence of splice variants or • Ion channels (TABLE 4) that a certain molecular interaction is interactions between the encoded proteins • Transport proteins (TABLE 5) indeed the one triggering the effect(s). from gene sequences alone, and the fact • DNA/RNA and the ribosome (TABLE 6) In this respect, knockout mice are proving that the function of most of the DNA in • Targets of monoclonal antibodies increasingly useful. For example, a lack of the genome remains unclear. In 1997, (TABLE 7) effect of a drug in mice lacking a particular when 100,000 protein-coding sequences • Various physicochemical mechanisms target can provide strong support that the were hypothesized to exist in the human (TABLE 8) effects of the drug are mediated by that target genome, Drews and Ryser estimated the • Unknown mechanism of action (BOX 1) (for a review on knockout mice in target number of molecular targets ‘hit’ by all validation, see REF. 5). marketed drug substances to be only 482 The nature of drug targets We therefore considered the construction (REF. 1). In 2002, after the sequencing of the A prerequisite for counting the number of of knockout animals that lack the target, human genome, others arrived at ~8,000 targets is defining what a target is. Indeed, with pertinent observation of effects, strong targets of pharmacological interest, of this is the crucial, most difficult and also proof or disproof for a certain mechanism which nearly 5,000 could be potentially most arbitrary part of the present approach. of action. In the case of receptors, we hit by traditional drug substances, nearly For the purpose of this paper, we consider a regarded the availability and testing of 2,400 by antibodies and ~800 by protein target to be a molecular structure (chemically both agonists and antagonists (and/or pharmaceuticals2. And on the basis of definable by at least a molecular mass) that inverse agonists) proof for a mechanism. ligand-binding studies, 399 molecular will undergo a specific interaction with In the case of enzyme inhibitors (for example, targets were identified belonging to 130 chemicals that we call drugs because they are cyclooxygenase inhibitors), molecular protein families, and ~3,000 targets for administered to treat or diagnose a disease. interactions and effects of structurally small-molecule drugs were predicted to The interaction has a connection with the unrelated substances that are largely exist by extrapolations from the number clinical effect(s). identical were considered proof of the of currently identified such targets in the This definition implies several con- mechanism. In cases where a drug inter- human genome3. straints. First, the medicinal goal excludes action on the biochemical level was found, In summary, current target counts are pharmacological and biochemical tools but the biochemical pathway was not yet of the order of 102, whereas estimations of from the present approach. Second, a major known to be connected with the observed the number of potential drug targets are an constraint is a lack of technique. Life, includ- drug effect, the target was not counted. For order of magnitude higher. In this paper, we ing disease, is dynamic, but as we do not yet antipsychotic drugs in particular, a plethora consider the nature of drug targets, and use a directly observe the interactions of drugs of target receptors and receptor subtypes classification based on this consideration, and and targets, and only partly notice the sub- are known and discussed (see PDSP Ki a list of approved drug substances (TABLES 1–8, sequent biochemical ‘ripples’ they produce; Database in Further information and BOX 1), to estimate the number of known drug we are generally limited to ‘still life’ (for BOX 2). However, extensive discussion of targets, in the following categories: example, X-ray crystal structures) such issues is outside the scope of an article
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 821 PERSPECTIVES
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 5α-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 Δ14 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/PDGFRβ/KIT/FLT3 Sunitinib66 VEGFR2/PDGFRβ/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, γ-amino butyric acid; HMG-CoA, 3-hydroxy-3-methyl-glutaryl coenzyme A; PDGFR, platelet-derived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.
822 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
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 β-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) α-glycosidase inhibitor Zanamivir, oseltamivir91 Glycosidases (human) α-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 Δ8,7 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-β-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.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 823 PERSPECTIVES
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 VAMP–synaptobrevin, 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, drug–target 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 target–effect 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 β-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 (γ-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 β-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 drug–drug 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 receptor–receptor 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
824 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
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 1–8, 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 β-sympatholytic agent, but it has neither an absolute selectivity for an adrenoceptor subtype nor to targets. In TABLES 1–8, 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 α-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 BCR–ABL 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 drug’s 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 (ligand–receptor). 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 efficient”18. 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.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 825 PERSPECTIVES
Table 3a | Receptors Type Activity of drug Drug examples Direct ligand-gated ion channel receptors 140 GABAA receptors Barbiturate binding site agonists Barbiturate 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 derivatives152,153 154 Muscarinic receptor M3 antagonists Darifenacine Adenosine receptors Agonists Adenosine155 156 Adenosine A1 receptor agonists Lignans from valerian
Adenosine A1 receptor antagonists Caffeine, theophylline 157 Adenosine A2A receptor antagonists Caffeine, theophylline Adrenoceptors158,159 Agonists Adrenaline, noradrenaline, ephedrine α α Xylometazoline 1- and 2-receptors agonists α Ergotamine160 1-receptor antagonists α Methyldopa (as methylnoradrenaline) 2-receptor, central agonists β-adrenoceptor antagonists Isoprenaline β Propranolol, atenolol 1-receptor antagonists β Salbutamol 2-receptor agonists β Propranolol 2-receptor antagonists 161 Angiotensin receptors AT1-receptors antagonists Sartans Calcium-sensing receptor Agonists Strontium ions162 Allosteric activators Cinacalcet163 164 Cannabinoid receptors CB1- and CB2-receptors agonists Dronabinol Cysteinyl-leukotriene receptors Antagonists Montelukast165 Dopamine receptors166 Dopamine receptor subtype direct agonists Dopamine, levodopa
D2, D3 and D4 agonists Apomorphine
D2, D3 and D4 antagonists Chlorpromazine, fluphenazine, haloperidol, metoclopramide, ziprasidone 167 Endothelin receptors (ETA, ETB) Antagonists Bosentan 168 GABAB receptors Agonists Baclofen Glucagon receptors Agonists Glucagon169 Glucagon-like peptide-1 receptor Agonists Exenatide170 171 Histamine receptors H1-antagonists Diphenhydramine 172 H2-antagonists Cimetidine Opioid receptors173,174 μ-opioid agonists Morphine, buprenorphine μ-, κ- and δ-opioid antagonists Naltrexone κ-opioid antagonists Buprenorphine
175 Neurokinin receptors NK1 receptor antagonists Aprepitant GABA, γ-amino butyric acid; NMDA, N-methyl-d-aspartate.
826 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
Table 3b | Receptors Type Activity of drug Drug examples Prostanoid receptors Agonists Misoprostol, sulprostone, iloprost176 Prostamide receptors Agonists Bimatoprost177 178 Purinergic receptors P2Y12 antagonists Clopidogrel Serotonin receptors Subtype-specific (partial) agonists Ergometrine, ergotamine160 179 5-HT1A partial agonists Buspirone 180 5-HT1B/1D agonists Triptans 181 5-HT2A antagonists Quetiapine, ziprasidone 182 5-HT3antagonists Granisetron 183 5-HT4 partial agonists Tegaserode Vasopressin receptors184 Agonists Vasopressin 185 V1 agonists Terlipressin
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 TNFα 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 Oestrogen receptor199 Agonists Oestrogens (Partial) antagonists Clomifene Antagonists Fulvestrant Modulators Tamoxifen, raloxifene200 Androgen receptor201,202 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 RARα agonists Isotretinoin209 RARβ agonists Adapalene, isotretinoin210 RARγ agonists Adapalene, isotretinoin210 Peroxisome proliferator-activated PPARα agonists Fibrates211,212 receptor (PPAR) PPARγ agonists Glitazones213 Thyroid hormone receptors Agonists l-Thyroxine214 ACTH, adrenocorticotropic hormone.
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 827 PERSPECTIVES
Table 4 | Ion channels substances included in the thirteenth Model List of Essential Medicines published by the Type Activity of drug Drug examples World Health Organization19 (excluding Voltage-gated Ca2+ channels the categories: vitamins, minerals, oxygen General Inhibitor Oxcarbazepine216 as a narcotic gas, and diagnostics); drug In Schistosoma sp. Inhibitor Praziquantel217 substances included in the FDA’s Approved Drug Products list (25th edition, 2005)20; L-type channels Inhibitor Dihydropyridines, diltiazem, lercanidipine, all newly developed drugs from the past pregabalin, verapamil218–223 5 years introduced on the German market21; 224 T-type channels Inhibitor Succinimides and drugs approved by the FDA in 2004 K+ channels225 with a new mechanism of action, again Epithelial K+ Opener Diazoxide, minoxidil226,227 excluding substitution therapeuticals22. We channels Inhibitor Nateglinide, sulphonylureas228,229 checked the resulting list against the lists 1 Voltage-gated K+ Inhibitor Amiodarone230 of targets in Drews and Ryser’s paper , a channels list of enzyme targets in the supplemental 23 Na+ channels material to Robertson’s paper , and a
+ compilation of receptors produced for Epithelial Na Inhibitor Amiloride, bupivacaine, lidocaine, procainamide, 24 channels (ENaC)231 quinidine nomenclature purposes , and we further supplemented our list using the current Voltage-gated Na+ Inhibitor Carbamazepine, flecainide, lamotrigine, phenytoin, channels propafenone, topiramate, valproic acid232–239 edition of Mutschler’s German textbook Drug Actions25. Ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family In this way, TABLES 1–8, BOX 1 include Ryanodine Inhibitor Dantrolene240,241 only those targets relevant for the effect of receptors drugs currently on the market. For drug Transient receptor potential Ca2+ channel (TRP-CC) family substances or classes in the lists, selected TRPV1 receptors Inhibitor Acetaminophen (as arachidonylamide)242 references are given that are concerned with the mechanism of action; the references are Cl– channels243 arranged by target family and subfamily, – 244 Cl channel Inhibitor (mast cells) Cromolyn sodium and within the subfamilies, alphabetically. Opener (parasites) Ivermectin245 New targets and mechanisms of action TRPV, transient receptor potential vanilloid. were not listed if a corresponding drug that interacts with the target has not yet been A further criterion needed for the full target(s) of an approved drug substance. marketed. Drugs currently undergoing categorization of drug substances according We filled the list shown in TABLES 1–8, clinical trials have been excluded for the to their target is the anatomical localization BOX 1 by including the following drugs and sake of briefness and also because of the of the target. This is essential for a differen- their corresponding main targets: all numerous status fluctuations of such drugs. tiation between substances with the same biochemical target, but a different organ specificity (for example, nifedipine and Table 5 | Transport proteins (uniporters, symporters and antiporters) verapamil are both L-type calcium channel Type246 Activity of drug Drug examples inhibitors; the former interacts primarily Cation-chloride Thiazide-sensitive NaCl Thiazide diuretics248 with vascular calcium channels and the cotransporter (CCC) symporter, human inhibitor family247 latter with cardiac calcium channels). Bumetanide-sensitive NaCl/KCl Furosemide249 However, in the tables, we chose not to symporters, human inhibitor include this criterion as it would have made Na+/H+ antiporters Inhibitor Amiloride, triamterene250–252 the list more cumbersome. Proton pumps Ca2+-dependent ATPase Artemisinin and derivatives253 (PfATP6; Plasmodia) inhibitor Categorization of current drugs. We began by sorting substances according to their H+/K+-ATPase inhibitor Omeprazole254 target, considering the following biochemi- Na+/K+ ATPase Inhibitor Cardiac glycosides255 cal structures to be target families: enzymes Eukaryotic (putative) sterol Niemann-Pick C1 like 1 Ezetimibe256 (TABLE 1); substrates, metabolites and proteins transporter (EST) family (NPC1L1) protein inhibitor (TABLE 2); receptors (TABLE 3); ion channels Neurotransmitter/Na+ Serotonin/Na+ symporter Cocaine, tricyclic (TABLE 4); transport proteins (TABLE 5); symporter (NSS) family257,258 inhibitor antidepressants, paroxetine257–260 DNA/RNA and the ribosome (TABLE 6); targets Noradrenaline/Na+ symporter Bupropion, venlafaxine261,262 of monoclonal antibodies (TABLE 7); various inhibitor physicochemical mechanisms (TABLE 8); and Dopamine/Na+ symporter Tricyclic antidepressants, (BOX 1) unknown mechanism of action . inhibitor cocaine, amphetamines257,258 Within the families, individual enzymes, 263,264 receptors and so on were included if they Vesicular monoamine Reserpine transporter inhibitor were identified in the literature as the main
828 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
Table 6 | DNA/RNA and the ribosome — or is claimed to show — a therapeutic effect. It will also be the case that, as with the Target Activity of drug Example drugs ATC system, certain drug substances appear Nucleic acids more than once in the list. Indeed, it will DNA and RNA265 Alkylation Chlorambucil, cyclophosphamide, happen more often than in the ATC system, dacarbazine266–268 owing to the fact that some drug effects are Complexation Cisplatin269,270 based on the synergistic effects of more than one mechanism of action. Intercalation Doxorubicin271 Oxidative degradation Bleomycin272 The number of drug targets Strand breaks Nitroimidazoles273 At the level of target definition we chose, RNA Interaction with 16S-rRNA Aminoglycoside antiinfectives274 which is illustrated by the table rows, we counted 218 targets. The most prominent Interaction with 23S-rRNA Macrolide antiinfectives275 target families included hydrolases in the 23S-rRNA/tRNA/2-polypeptide Oxazolidinone antiinfectives276 enzyme family, GPCRs in the receptor complex family and voltage-gated Ca2+ channels in Spindle Inhibition of development Vinca alkaloids277 the ion-channel family. The usefulness of Inhibition of desaggregation Taxanes278 a target family in this count is probably a consequence of its commonness, the format Inhibition of mitosis — Colchicine279 of assays (with recent binding-affinity based 280 Ribosome assays having contributed little as yet), and 30S subunit (bacterial) Inhibitors Tetracyclines281 the nature of the diseases that affect the 50S subunit (bacterial) Inhibitors Lincosamides, quinupristin– developed world. dalfopristin282, 283 A large part of this paper is concerned with the nature of drug targets and the need to consider the dynamics of the drug–targets It should be noted that for a certain target, Of course, our list is an approximation. (plural intended) interactions, as these we did not include all drug substances And a categorization of compounds considerations were used to define what we that address it, but just a representative according to their mechanism of action will would eventually count. Many successful example of the structural classes in use. In inevitably lead to a group of remaining drugs drugs have emerged from the simplistic some cases, such as the β-lactams, we cited with proven clinical effectiveness, but an ‘one drug, one target, one disease’ approach the structural class instead of individual unknown molecular target. Such compounds that continues to dominate pharmaceutical representatives. We tried to name the first can, if at all, only hypothetically be classified thinking, and we have generally used this substance of a class, if it is still marketed. within the selected major groups. The ATC approach when counting targets here. A subdivision of the major groups classification system, with its systematic cat- However, there is an increasing readiness according to the ‘anatomy’ (cell type or egorization according to therapeutic aspects to challenge this paradigm29–32. We have physiological functional unit within which (for example, ‘analgesics’) does not have this discussed its constraints and limitations the target is located and acted on by the problem, as every substance in the list shows in light of the emerging network view of drug) and the substance class has been carried out in just a few cases for which the literature seemed to be unanimous about Table 7 | Targets of monoclonal antibodies the identification and relevance of such a Target Agent subdivision. In order to keep TABLES 1–8, Vascular endothelial growth factor Bevacizumab284,285 BOX 1 readable, the main focus has been Lymphocyte function-associated antigen 1 Efalizumab286 given to the classification of the substance according to its biochemical target. Epidermal growth factor receptor Cetuximab284,287 A categorization going into further detail Human epidermal growth factor receptor 2 Trastuzumab288 is outside the scope of this article, although Immunoglobulin E (IgE) Omalizumab289 of course obtaining further molecular and CD-3 Muromonab-CD3290 cellular detail is possible in some cases. For example, transport proteins have been CD-20 Rituximab, ibritumomab tiuxetan, 131 291,292 subclassified in great detail26,27, and target I-tositumomab lists have been produced for cancer drugs28. CD-33 Gemtuzumab293 An extensive list of affinities of CNS drugs CD-52 Alemtuzumab294 for vast numbers of targets is also available F protein of RSV subtypes A and B Palivizumab295 online at the PDSP Database (see Further 296,297 information). The latter list illustrates well CD-25 Basiliximab, daclizumab the point discussed previously: that in many Tumour-necrosis factor-α Adalimumab, infliximab298,299 cases it will not help to know a single target, Glycoprotein IIb/IIIa receptor Abciximab300 because the clinical effect is caused by α Natalizumab301 patterns of target interactions. 4-Integrin subunit
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 829 PERSPECTIVES
15. Gohlke, H. & Klebe, G. Approaches to the Table 8 | Various physicochemical mechanisms description and prediction of the binding affinity of small-molecule ligands to macromolecular receptors. Mechanism Agent Angew. Chem. Int. Ed. Engl. 41, 2644–2676 (2002). Ion exchange Fluoride 16. Schwabe, U. ATC-Code (Wissenschaftliches Institut der Acid binding Magnesium hydroxide, aluminium hydroxide AOK, Bonn, Germany, 1995). 17. Imming, P. et al. A classification of drug substances Adsorptive Charcoal, colestyramine according to their mechanism of action. Pharmazie 59, 579–589 (2004). Adstringent Bismuth compounds 18. Swinney, D. C. Biochemical mechanisms of drug action: what does it take for success? Nature Rev. Surface-active Simeticone, chlorhexidine, chloroxylene Drug Discov. 3, 801–808 (2004). 19. World Health Organization. The Essential Medicines Surface-active on cell membranes Coal tar List [online],
830 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
43. Smith, W. L. & Song, I. The enzymology of 70. Painter, G. R., Almond, M. R., Mao, S. & Liotta, D. C. 94. Wynn, G. H., Zapor, M. J., Smith, B. H., Wortmann, G., prostaglandin endoperoxide H synthases-1 and-2. Biochemical and mechanistic basis for the activity of Oesterheld, J. R., Armstrong, S. C. & Cozza, K. L. Prostaglandins Other Lipid Mediat. 68–69, 115–28 nucleoside analogue inhibitors of HIV reverse Antiretrovirals, part 1: overview, history, and focus on (2002). transcriptase. Curr. Top. Med. Chem. 4, 1035–1044 protease inhibitors. Psychosomatics 45, 262–270 44. Hogestatt, E. D. et al. Conversion of acetaminophen (2004). (2004). to the bioactive N-acyl phenolamine AM404 via fatty 71. Zapor, M. J., Cozza, K. L., Wynn, G. H., 95. Wegner, J. Biochemistry of serine protease inhibitors acid amide hydrolase-dependent arachidonic acid Wortmann, G. W. & Armstrong, S. C. Antiretrovirals, and their mechanisms of action: a review. J. Extra. conjugation in the nervous system. J. Biol. Chem. Part II: focus on non-protease inhibitor antiretrovirals Corpor. Technol. 35, 326–338 (2003). 280, 31405–31412 (2005). (NRTIs, NNRTIs, and fusion inhibitors). 96. Konaklieva, M. I. β-lactams as inhibitors of serine 45. Mann, K. G. The challenge of regulating anticoagulant Psychosomatics 45, 524–535 (2004). enzymes. Curr. Med. Chem. Anti-Infect. Agents 1, drugs: Focus on warfarin. Am. Heart J. 149 (Suppl 1), 72. Bell, C., Matthews, G. V. & Nelson, M. R. Non- 215–238 (2002). 36–42 (2005). nucleoside reverse transcriptase inhibitors — an 97. Nicolau, K. C., Boddy, C. N. C., Brase, S. & Winssinger, 46. Miller, R. W. Aromatase inhibitors: mechanism of overview. Int. J. STD AIDS 14, 71–77 (2003). N. Chemistry, biology, and medicine of the action and role in the treatment of breast cancer. 73. Young, S. D. et al. L-743,726 (DMP-266): a novel, glycopeptide antibiotics. Angew. Chem., Int. Ed. Engl. Semin. Oncol. 30 (4 Suppl 14), 3–11 (2003). highly potent nonnucleoside inhibitor of the human 38, 2096–2152 (1999). 47. Maertens, J. A. History of the development of azole immunodeficiency virus type 1 reverse transcriptase. 98. Matagne, A., Dubus, A., Galleni, M. & Frere, J. M. derivatives. Clin. Microbiol. Infect. 10 (Suppl 1), 1–10 Antimicrob. Agents Chemother. 39, 2602–2605 The β-lactamase cycle. Nat. Prod. Rep. 16, 1–19 (2004). (1995). (1999). 48. Klotz, U. The role of aminosalicylates at the beginning 74. Earnshaw, D. L., Bacon, T. H., Darlison, S. J., 99. Hirsh, J., Raschke, R., Warkentin, T. E., Dalen, J. E., of the new millennium in the treatment of chronic Edmonds, K., Perkins, R. M. & Vere Hodge, R. A. Deykin, D. & Poller, L. Heparin: mechanism of action, inflammatory bowel disease. Eur. J. Clin. Pharmacol. Mode of antiviral action of penciclovir in MRC-5 cells pharmacokinetics, dosing considerations, monitoring, 56, 353–362 (2000). infected with herpes simplex virus type 1 (HSV-1), efficacy and safety. Chest 108 (Suppl. 4), 258–275 49. Parnes, S. M. The role of leukotriene inhibitors in HSV-2, and varicella-zoster virus. Antimicrob. Agents (1995). patients with paranasal sinus disease. Curr. Opin. Chemother. 36, 2747–2757 (1992). 100. Nader, H. B., Lopes, C. C., Rocha, H. A., Santos, E. A. Otolaryngol. Head Neck. Surg. 11, 184–191 75. Walther, M. M., Trahan, E. E., Cooper, M., Venzon, D. & Dietrich, C. P. Heparins and heparinoids: occurrence, (2003). & Linehan, W. M. Suramin inhibits proliferation and structure and mechanism of antithrombotic and 50. Cooper, D. S. Antithyroid drugs. N. Engl. J. Med. 352, DNA synthesis in transitional carcinoma cell lines. hemorrhagic activities. Curr. Pharm. Des. 10, 951–966 905–917 (2005). J. Urol. 152, 1599–1602 (1994). (2004). 51. Allison, A. C. & Eugui, E. M. Mycophenolate mofetil 76. Gurvich, N., Tsygankova, O. M., Meinkoth, J. L. & 101. Wolvekamp, M. C. & de Bruin, R. W. Diamine oxidase: and its mechanisms of action. Immunopharmacology Klein, P. S. Histone deacetylase is a target of valproic an overview of historical, biochemical and functional 47, 85–118 (2000). acid-mediated cellular differentiation. Cancer Res. 64, aspects. Dig. Dis. 12, 2–14 (1994). 52. Stancu, C. & Sima, A. Statins: mechanism of action 1079–1086 (2004). 102. Weitz, J. I., Stewart, R. J. & Fredenburgh, J. C. and effects. J. Cell. Mol. Med. 5, 378–387 (2001). 77. Angehagen, M., Ben-Menachem, E., Ronnback, L. Mechanism of action of plasminogen activators. 53. Bull, H. G. et al. Mechanism-based inhibition of human & Hansson, E. Novel mechanisms of action of three Thromb. Haemost. 82, 974–982 (1999). steroid 5α-reductase by finasteride: enzyme-catalyzed antiepileptic drugs, vigabatrin, tiagabine, and 103. Bajaj, A. P. & Castellino, F. J. Activation of human formation of NADP-Dihydrofinasteride, a potent topiramate. Neurochem. Res. 28, 333–340 plasminogen by equimolar levels of streptokinase. bisubstrate analog inhibitor. J. Am. Chem. Soc. 118, (2003). J. Biol. Chem. 252, 492–498 (1977). 2359–2365 (1996). 78. Buchdunger, E. et al. ABL protein-tyrosine kinase 104. Spronk, H. M., Govers-Riemslag, J. W. & ten Cate, H. 54. Matthews, D. A. et al. Refined crystal structures of inhibitor STI571 Inhibits in vitro signal transduction The blood coagulation system as a molecular machine. Escherichia coli and chicken liver dihydrofolate mediated by c-Kit and platelet-derived growth factor Bioessays 25, 1220–1228 (2003). reductase containing bound trimethoprim. J. Biol. receptors. J. Pharmacol. Exp. Ther. 295, 139–145 105. Bauer, K. A. Fondaparinux sodium: a selective Chem. 260, 381–391 (1985). (2000). inhibitor of factor Xa. Am. J. Health Syst. Pharm. 58 55. Goldman, I. D. & Zhao, R. Molecular, biochemical, and 79. Minna, J. D. & Dowell, J. Erlotinib hydrochloride. (Suppl 2), 14–17 (2001). cellular pharmacology of pemetrexed. Semin. Oncol. Nature Rev. Drug Discov. 4, S14–S15 (2005). 106. Nemec, K. & Schubert-Zsilavecz, M. From teprotide to 29 (6 Suppl 18), 3–17 (2002). 80. Yoon, H. J. et al. Crystallization and preliminary captopril. Rational design of ACE inhibitors. Pharm. 56. Anderson, A. C. Targeting DHFR in parasitic protozoa. X-ray crystallographic analysis of UDP-N- Unserer Zeit 32, 11–16 (2003). Drug Discov. Today 10, 121–128 (2005). acetylglucosamine enolpyruvyl transferase from 107. Pastel, D. A. Imipenem-cilastatin sodium, a broad- 57. Fox, R. I. Mechanism of action of leflunomide in Haemophilus influenzae in complex with UDP-N- spectrum carbapenem antibiotic combination. rheumatoid arthritis. J. Rheumatol. Suppl. 53, 20–26 acetylglucosamine and fosfomycin. Mol. Cell 19, Clin. Pharm. 5, 719–736 (1986). (1998). 398–401 (2005). 108. Bondeson, J. The mechanisms of action of disease- 58. Heath, R. J., White, S. W. & Rock, C. O. Inhibitors of 81. El Zoeiby, A., Sanschagrin, F. & Levesque, R. C. Structure modifying antirheumatic drugs: a review with fatty acid synthesis as antimicrobial and function of the Mur enzymes: development of novel emphasis on macrophage signal transduction and the chemotherapeutics. Appl. Microbiol. Biotechnol. 58, inhibitors. Mol. Microbiol. 47, 1–12 (2003). induction of proinflammatory cytokines. Gen. 695–703 (2002). 82. Goto, M. et al. M. Structural determinants for Pharmacol. 29, 127–150 (1997). 59. Ryder, N. S. The mechanism of action of terbinafine. branched-chain aminotransferase isozyme specific 109. Adnane, L., Trail, P. A., Taylor, I., Wilhelm, S. M. Clin. Exp. Dermatol. 14, 98–100 (1989). inhibition by the anticonvulsant drug gabapentin. Sorafenib (BAY 43–9006, Nexavar), a dual-action 60. Barrett-Bee, K. & Dixon, G. Ergosterol biosynthesis J. Biol. Chem. 280, 37246–37256 (2005). inhibitor that targets RAF/MEK/ERK pathway in tumor inhibition: a target for antifungal agents. Acta 83. Adams, J. The proteasome: a suitable antineoplastic cells and tyrosine kinases VEGFR/PDGFR in tumor Biochim. Pol. 42, 465–479 (1995). target. Nature Rev. Cancer 4, 349–360 (2004). vasculature. Methods Enzymol. 407, 597–612 (2005). 61. Borges, F., Fernandes, E. & Roleira, F. Progress 84. Sugimoto, H., Ogura, H., Arai, Y., Limura, Y. & 110. De la Baume, S., Brion, F., Dam-Trung-Tuong, M. & towards the discovery of xanthine oxidase inhibitors. Yamanishi, Y. Research and development of donepezil Schwartz, J. C. Evaluation of enkephalinase inhibition Curr. Med. Chem. 9, 195–217 (2002). hydrochloride, a new type of acetylcholinesterase in the living mouse, using [3H]acetorphan as a probe. 62. Brownlee, J. M., Johnson-Winters, K., Harrison, D. H. inhibitor. Jpn. J. Pharmacol. 89, 7–20 (2002). J. Pharmacol. Exp. Ther. 247, 653–660 (1988). & Moran, G. R. Structure of the ferrous form of 85. Kwong, T. C. Organophosphate pesticides: 111. Reynolds, N. J. & Al-Daraji, W. I. Calcineurin inhibitors (4-hydroxyphenyl)pyruvate dioxygenase from biochemistry and clinical toxicology. Ther. Drug Monit. and sirolimus: mechanisms of action and applications Streptomyces avermitilis in complex with the 24, 144–149 (2002). in dermatology. Clin. Exp. Dermatol. 27, 555–561 therapeutic herbicide, NTBC. Biochemistry 43, 86. Fisone, G., Borgkvist, A. & Usiello, A. Caffeine as a (2002). 6370–6377 (2004). psychomotor stimulant: mechanism of action. Cell. 112. Patel, S., Martinez-Ripoll, M., Blundell, T. L. & 63. Yarbro, J. W. Mechanism of action of hydroxyurea. Mol. Life Sci. 61, 857–872 (2004). Albert, A. Structural enzymology of Li+-sensitive/ Semin. Oncol. 19 (Suppl 9), 1–10 (1992). 87. Honerjager, P. & Nawrath, H. Pharmacology of Mg2+-dependent phosphatases. J. Mol. Biol. 320, 64. Hofmann, J. Modulation of protein kinase C in bipyridine phosphodiesterase III inhibitors. Eur. J. 1087–1094 (2002). antitumor treatment. Rev. Physiol. Biochem. Anaesthesiol. Suppl. 5, 7–14 (1992). 113. Spiegelberg, B. D, Dela Cruz, J., Law, T. H & York, J. D. Pharmacol. 142, 1–96 (2001). 88. Kaneda, T., Takeuchi, Y., Matsui, H., Shimizu, K., Alteration of lithium pharmacology through 65. Jendrossek, V. & Handrick, R. Membrane targeted Urakawa, N. & Nakajyo, S. Inhibitory mechanism of manipulation of phosphoadenosine phosphate anticancer drugs: potent inducers of apoptosis and papaverine on carbachol-induced contraction in metabolism. J. Biol. Chem. 280, 5400–5405 (2005). putative radiosensitisers. Curr. Med. Chem. Anti-Canc. bovine trachea. J. Pharmacol. Sci. 98, 275–282 114. Tiede, I. et al. CD28-dependent Rac1 activation is the Agents 3, 343–353 (2003). (2005). molecular target of azathioprine in primary human 66. Atkins, M., Jones, C. A. & Kirkpatrick, P. Sunitinib 89. Corbin, J. D. & Francis, S. H. Molecular biology and CD4+ T lymphocytes. J. Clin. Invest. 111, 1133–1145 maleate. Nature Rev. Drug Discov. 5, 279–280 pharmacology of PDE-5-inhibitor therapy for erectile (2003). (2006). dysfunction. J. Androl. 24 (Suppl 6), 38–41 (2003). 115. El Ghachi, M., Bouhss, A., Blanot, D. & Mengin- 67. Schlünzen, F. et al. Structural basis for the 90. Beutler, A. S., Li, S., Nicol, R. & Walsh, M. J. Lecreulx, D. The bacA gene of Escherichia coli interaction of antibiotics with the peptidyl Carbamazepine is an inhibitor of histone deacetylases. encodes an undecaprenyl pyrophosphate phosphatase transferase centre in eubacteria. Nature 413, Life Sci. 76, 3107–3115 (2005). activity. J. Biol. Chem. 279, 30106–30113 (2004). 814–821 (2001). 91. Calfee, D. P. & Hayden, F. G. New approaches to 116. Bartholini, G. & Pletscher, A. Decarboxylase inhibitors. 68. Mannisto, P. T. et al. Characteristics of catechol influenza chemotherapy: neuraminidase inhibitors. Pharmacol. Ther. [B]. 1, 407–421 (1975). O-methyl-transferase (COMT) and properties of Drugs 56, 537–553 (1998). 117. Supuran, C. T., Scozzafava, A. & Casini, A. Carbonic selective COMT inhibitors. Prog. Drug Res. 39, 92. Krasikov, V. V., Karelov, D. V. & Firsov, L. M. alpha- anhydrase inhibitors. Med. Res. Rev. 23, 146–189 291–350 (1992). Glucosidases. Biochemistry (Mosc). 66, 267–281 (2003). 69. Komo, K., Oizumi, K. & Oka, S. Mode of action of (2001). 118. Sonneville, A. Hypostamine (tritoqualine), a synthetic rifampin on mycobacteria. Am. Rev. Respir. Dis. 107, 93. Guerciolini, R. Mode of action of orlistat. Int. J. Obes. reference antihistaminic. Allerg. Immunol. (Paris) 20, 1006–1012 (1973). Relat. Metab. Disord. 21 (Suppl 3), 12–23 (1997). 365–368 (1988).
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 831 PERSPECTIVES
119. Huang, Y., Pledgie, A., Casero, R. A. Jr. & Davidson, NE. 149. Dahchour, A. & De Witte, P. Ethanol and amino 178. Herbert, J. M. & Savi, P. P2Y12, a new platelet ADP Molecular mechanisms of polyamine analogs in cancer acids in the central nervous system: assessment of receptor, target of clopidogrel. Semin. Vasc. Med. 3, cells. Anticancer Drugs 16, 229–241 (2005). the pharmacological actions of acamprosate. 113–122 (2003). 120. Chen, Z. et al. An essential role for mitochondrial Prog. Neurobiol. 60, 343–362 (2000). 179. Tunnicliff, G. Molecular basis of buspirone’s anxiolytic aldehyde dehydrogenase in nitroglycerin bioactivation. 150. Kress, H. G. Mechanisms of action of ketamine. action. Pharmacol. Toxicol. 69, 149–156 (1991). Proc. Natl Acad. Sci. USA 102, 12159–12164 (2005). Anaesthesist 46 (Suppl. 1), 8–19 (1997). 180. Ahn, A. H. & Basbaum, A. I. Where do triptans act in 121. Thatcher, G. R., Nicolescu, A. C., Bennett, B. M. & 151. Gautam, D. et al. Cholinergic stimulation of salivary the treatment of migraine? Pain 115, 1–4 (2005). Toader, V. Nitrates and NO release: contemporary secretion studied with M1 and M3 muscarinic 181. Meltzer, H. Y., LI, Z., Kaneda, Y. & Ichikawa, J. aspects in biological and medicinal chemistry. receptor single- and double-knockout mice. Mol. Serotonin receptors: their key role in drugs to treat Free Rad. Biol. Medic. 37, 1122–1143 (2004). Pharmacol. 66, 260–267 (2004). schizophrenia. Prog. Neuropsychopharmacol. Biol. 122. Ignarro, L. J. After 130 years, the molecular 152. Eglen, R. M., Choppin, A. & Watson, N. Therapeutic Psychiatry 27, 1159–1172 (2003). mechanism of action of nitroglycerin is revealed. opportunities from muscarinic receptor research. 182. Blower, P. R. Granisetron: relating pharmacology to Proc. Natl Acad. Sci. USA 99, 7816–7817 (2002). Trends Pharmacol. Sci. 22, 409–414 (2001) clinical efficacy. Support Care Cancer 11, 93–100 123. Kukovetz, W. R. & Holzmann, S. Cyclic GMP as the 153. Pitschner, H. F. et al. Selective antagonists reveal (2003). mediator of molsidomine-induced vasodilatation. different functions of M cholinoceptor subtypes in 183. Galligan, J. J. & Vanner, S. Basic and clinical Eur. J. Pharmacol. 122, 103–109 (1986). humans. Trends Pharmacol. Sci. Suppl. 92–96 (1989). pharmacology of new motility promoting agents. 124. Fenn, T. D., Stamper, G. F., Morollo, A. A. & 154. Hegde, S. S. et al. Functional role of M2 and M3 Neurogastroenterol. Motil. 17, 643–653 (2005). Ringe, D. A side reaction of alanine racemase: muscarinic receptors in the urinary bladder of rats 184. Chini, B. & Fanelli, F. Molecular basis of ligand binding transamination of cycloserine. Biochemistry 42, in vitro and in vivo. Br. J. Pharmacol. 120, and receptor activation in the oxytocin and 5775–5783 (2003). 1409–1418. (1997). vasopressin receptor family. Exp. Physiol. 85 Spec. No 125. Drlica, K. & Malik, M. Fluoroquinolones: action and 155. Fredholm, B. B., Chen, J. F., Masino, S. A. & 59S-66S (2000). resistance. Curr. Top. Med. Chem. 3, 249–282 (2003). Vaugeois, J. M. Actions of adenosine at its receptors 185. Kam, P. C., Williams, S. & Yoong, F. F. Vasopressin and 126. Pizzolato, J. F. & Saltz, L. B. The camptothecins. in the CNS: insights from knockouts and drugs. Annu. terlipressin: pharmacology and its clinical relevance. Lancet 361, 2235–2242 (2003). Rev. Pharmacol. Toxicol. 45, 385–412 (2005). Anaesthesia 59, 993–1001 (2004). 127. Meresse, P., Dechaux, E., Monneret, C. & 156. Schumacher, B., Scholle, S., Holzl, J., Khudeir, N., 186. Kopchick, J. J. Discovery and mechanism of action of Bertounesque, E. Etoposide: discovery and medicinal Hess, S. & Muller, C. E. Lignans isolated from valerian: pegvisomant. Eur. J. Endocrinol. 148 (Suppl. 2), chemistry. Curr. Med. Chem. 11, 2443–2466 (2004). identification and characterization of a new olivil 21–25 (2003).
128. Polak-Wyss, A., Lengsfeld, H., Oesterhelt, G. Effect of derivative with partial agonistic activity at A1 187. Zhu, Y. & D’Andrea, A. D. The molecular physiology of oxiconazole and Ro 14–4767/002 on sterol pattern adenosine receptors. J. Nat. Prod. 65, 1479–1485 erythropoietin and the erythropoietin receptor. in Candida albicans. Sabouraudia 23, 433–441 (2002). Curr. Opin. Hematol. 1, 113–118 (1994). (1985). 157. Fisone, G., Borgkvist, A. & Usiello, A. Caffeine as a 188. Crawford, J. Neutrophil growth factors. Curr. Hematol. 129. Achari, A. et al. Crystal structure of the anti-bacterial psychomotor stimulant: mechanism of action. Cell. Rep. 1, 95–102 (2002). sulfonamide drug target dihydropteroate synthase. Mol. Life Sci. 61, 857–872 (2004). 189. Sylvester, R. K. Clinical applications of colony- Nature Struct. Biol. 4, 490–497 (1997). 158. Ruffolo, R. R., Bondinell, W. Jr. & Hieble, J. P. α- and stimulating factors: a historical perspective. Am. J. 130. Longley, D. B., Harkin, D. P. & Johnston, P. G. β-adrenoceptors: from the gene to the clinic. 2. Health Syst. Pharm. 59, Suppl 2, S6–12 (2002) 5-fluorouracil: mechanisms of action and clinical Structure–activity relationships and therapeutic 190. Fleischmann, R., Stern, R. & Iqbal, I. Anakinra: an strategies. Nature Rev. Cancer 3, 330–338 (2003). applications. J. Med. Chem. 38, 3681–3716 (1995). inhibitor of IL-1 for the treatment of rheumatoid 131. Gilli, R., Lopez, C., Sari, J. C. & Briand, C. 159. Hieble, J. P., Bondinell, W. & Ruffolo, R. R. From the arthritis. Expert. Opin. Biol. Ther. 4, 1333–1344 Thermodynamic study of the interaction of gene to the clinic. 1. Molecular biology and (2004). methotrexate, its metabolites, and new antifolates adrenoceptor classification. J. Med. Chem. 38, 191. Schmidinger, M., Hejna, M. & Zielinski, C. C. with thymidylate synthase: influence of FdUMP. 3415–3444 (1995). Aldesleukin in advanced renal cell carcinoma. Expert. Biochem. Pharmacol. 40, 2241–2246 (1990). 160. Silberstein, S. D. The pharmacology of ergotamine and Rev. Anticancer Ther. 4, 957–80 (2004). 132. Su, J. G., Mansour, J. M. & Mansour, T. E. Purification, dihydroergotamine. Headache 37 (Suppl. 1), 15–25 192. Cole, P. & Rabasseda, X. The soluble tumor necrosis kinetics and inhibition by antimonials of recombinant (1997). factor receptor etanercept: a new strategy for the phosphofructokinase from Schistosoma mansoni. 161. Burnier, M. Angiotensin II type 1 receptor blockers. treatment of autoimmune rheumatic disease. Drugs Mol. Biochem. Parasitol. 81, 171–178 (1996). Circulation 13, 904–12 (2001). Today (Barc.) 40, 281–324 (2004). 133. Sehgal, S. N. Sirolimus: its discovery, biological 162. Brown, E. M. Is the calcium receptor a molecular 193. Topol, E. J., Byzova, T. V. & Plow, E. F. Platelet GPIIb- properties, and mechanism of action. Transplant. Proc. target for the actions of strontium on bone? IIIa blockers. Lancet 353, 227–231 (1999). 35 (Suppl 3), 7–14 (2003). Osteoporo. Int. 14 (Suppl 3), 25–34 (2003). 194. Accili, D., Nakae, J. & Flier, J. S. in Diabetes Mellitus — 134. Foley, M. & Tilley, L. Quinoline antimalarials: 163. Nemeth, E. F. et al. Pharmacodynamics of the type II A Fundamental and Clinical Text 3rd edn (eds LeRoith, mechanisms of action and resistance and prospects calcimimetic compound cinacalcet HCl. J. Pharmacol. D., Taylor, S. I. & Olefsky, J. M.) (Lippincott Williams & for new agents. Pharmacol. Ther. 79, 55–87 Exp. Ther. 308, 627–635 (2004). Wilkins, Philadelphia, 2003). (1998). 164. Grotenhermen, F. Pharmacology of cannabinoids. 195. Jiang, G. & Zhang, B. B. Modulation of insulin 135. Denning, D. W. Echinocandin antifungal drugs. Lancet Neuro. Endocrinol. Lett. 25, 14–23 (2004). signalling by insulin sensitizers. Biochem. Soc. Trans. 362, 1142–1151 (2003). 165. Nicosia, S. Pharmacodynamic properties of 33, 358–361 (2005) 136. McCormack, P. L. & Goa, K. L. Miglustat. Drugs 63, leukotriene receptor antagonists. Monaldi Arch. Chest 196. Rogerson, F. M, Brennan, F. E. & Fuller, P. J. 2427–2434 (2003). Dis. 54, 242–246 (1999) Mineralocorticoid receptor binding, structure and 137. Graham, M. L. Pegaspargase: a review of clinical 166. Vallone, D., Picetti, R. & Borrelli, E. Structure and function. Mol. Cell. Endocrinol. 217, 203–212 studies. Adv. Drug Deliv. Rev. 55, 1293–1302 function of dopamine receptors. Neurosci. Biobehav. (2004). (2003). Rev. 24, 125–132 (2000). 197. Necela, B. M. & Cidlowski, J. A. Crystallization of the 138. Pea, F. Pharmacology of drugs for hyperuricemia. 167. Clozel, M. et al. Pharmacological characterization of human glucocorticoid receptor ligand binding domain: Mechanisms, kinetics and interactions. Contrib. bosentan, a new potent orally active nonpeptide a step towards selective glucocorticoids. Trends Nephrol. 147, 35–46 (2005). endothelin receptor antagonist. J. Pharmacol. Exp. Pharmacol. Sci. 24, 58–61 (2003). 139. Dressler, D. & Adib Saberi, F. Botulinum toxin: Ther. 270, 228–235 (1994). 198. Li, X. & O’Malley, B. W. Unfolding the action of mechanisms of action. Eur. Neurol. 53, 3–9 (2005). 168. Hill, D. R. & Bowery, N. G. 3H-Baclofen and 3H-GABA progesterone receptors. J. Biol. Chem. 278,
140. Czapinski, P., Blaszczyk, B. & Czuczwar, S. J. bind to bicuculline-insensitive GABAB sites in rat brain. 39261–39264 (2003). Mechanisms of action of antiepileptic drugs. Curr. Top. Nature 290, 149–152 (1981). 199. Katzenellenbogen, B. S. et al. Molecular mechanisms Med. Chem. 5, 3–14 (2005). 169. Unson, C. G. Molecular determinants of glucagon of estrogen action: selective ligands and receptor
141. Wafford, K. A. GABAA receptor subtypes: any clues receptor signaling. Biopolymers 66, 218–235 (2002). pharmacology. J. Steroid Biochem. Mol. Biol. 74, to the mechanism of benzodiazepine dependence? 170. Keating, G. M. Exenatide. Drugs 65, 1681–1692 279–285 (2000). Curr. Opin. Pharmacol. 5, 47–52 (2005). (2005). 200. Levenson, A. S. & Jordan, V. C. Selective oestrogen
142. Hoffman, E. J. & Warren, E. W. Flumazenil: 171. Simons, F. E. Advances in H1-antihistamines. N. Engl. J. receptor modulation: molecular pharmacology for the a benzodiazepine antagonist. Clin. Pharm. 12, Med. 351, 2203–2217 (2004). millennium. Eur. J. Cancer 35, 1628–1639 (1999). 641–656 (1993). 172. Mills, J. G. & Wood, J. R. The pharmacology of 201. Gobinet, J., Poujol, N. & Sultan, Ch. Molecular action
143. Martin, R. J., Robertson, A. P. & Bjorn, H. Target sites histamine H2-receptor antagonists. Methods Find. of androgens. Mol. Cell. Endocrinol. 198, 15–24 of anthelmintics. Parasitology 114 (Suppl), 111–124 Exp. Clin. Pharmacol. 11 (Suppl 1), 87–95 (1989). (2002). (1997). 173. Pasternak, G. W. Molecular biology of opioid 202. Roy, A. K. et al. Androgen receptor: structural 144. Martin, R. J. Modes of action of anthelmintic drugs. analgesia. J. Pain Symptom. Manage. 29 (Suppl.) domains and functional dynamics after ligand-receptor Vet. J. 154, 11–34 (1997). S2–S9 (2005). interaction. Ann. N. Y. Acad. Sci. 949, 44–57 145. McManus, M. C. Neuromuscular blockers in surgery 174. Surratt, C. K. & Adams, W. R. G protein-coupled (2001). and intensive care, Part 1. Am. J. Health Syst. Pharm. receptor structural motifs: relevance to the opioid 203. Gao, W., Bohl, C. E. & Dalton, J. T. Chemistry and 58, 2287–2299 (2001). receptors. Curr. Top. Med. Chem. 5, 315–324 (2005). structural biology of androgen receptor. Chem. Rev. 146. Bowman, W. C. Neuromuscular block. Br. J. Pharmacol. 175. Diemunsch, P. & Grelot, L. Potential of substance P 105(9), 3352–3370 (2005). 147 S1, 277–286 (2006). antagonists as antiemetics. Drugs 60, 533–546 (2000). 204. Neumann, F. The antiandrogen cyproterone acetate: 147. Samochocki, M. et al. Galantamine is an allosterically 176. Narumiya, S., Sugimoto, Y. & Ushikubi, F. Prostanoid discovery, chemistry, basic pharmacology, clinical use potentiating ligand of the human α4/β2 nAChR. receptors: structures, properties, and functions. and tool in basic research. Exp. Clin. Endocrinol. 102, Acta Neurol. Scand. Suppl. 176, 68–73 (2000). Physiol. Rev. 79, 1193–1226 (1999). 1–32 (1994). 148. Rogawski, M. A. & Wenk, G. L. The 177. Krauss, A. H. & Woodward, D. F. Update on the 205. Carlberg, C. Current understanding of the function of neuropharmacological basis for the use of memantine mechanism of action of bimatoprost: a review and the nuclear vitamin D receptor in response to its in the treatment of Alzheimer’s disease. C. N. S. Drug discussion of new evidence. Surv. Ophthalmol. 49 natural and synthetic ligands. Recent Results Cancer Rev. (Fall) 9, 275–308 (2003). (Suppl. 1), 5–11 (2004). Res. 164, 29–42 (2003)
832 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc PERSPECTIVES
206. Pinette, K. V., Yee, Y. K., Amegadzie, B. Y. & Nagpal, S. 232. Ambrosio, A. F., Soares-Da-Silva, P., Carvalho, C. M. & 256. Garcia-Calvo, M. et al. The target of ezetimibe is Vitamin D receptor as a drug discovery target. Mini Carvalho, A. P. Mechanisms of action of Niemann-Pick C1-Like 1 (NPC1L1). Proc. Natl Acad. Rev. Med. Chem. 3, 193–204 (2003). carbamazepine and its derivatives, oxcarbazepine, BIA Sci. USA 102, 8132–8137 (2005). 207. Minucci, S. & Ozato, K. Retinoid receptors in 2–093, and BIA 2–024. Neurochem. Res. 27, 257. Goldberg, N. R., Beuming, T., Soyer, O. S., Goldstein, transcriptional regulation. Curr. Opin. Genet. Dev. 6, 121–130 (2002). R. A., Weinstein, H. & Javitch, J. A. Probing 567–574 (1996). 233. Falk, R. H. & Fogel, R. I. Flecainide. J. Cardiovasc. conformational changes in neurotransmitter 208. Zwermann, O., Schulte, D. M., Reincke, M. & Electrophysiol. 5, 964–981 (1994). transporters: a structural context. Eur. J. Pharmacol. Beuschlein, F. ACTH 1–24 inhibits proliferation of 234. Coulter, D. A. Antiepileptic drug cellular mechanisms 479, 3–12 (2003). adrenocortical tumors in vivo. Eur. J. Endocrinol. 153, of action: where does lamotrigine fit in? J. Child 258. Saier, Jr., M. H. A functional-phylogenetic system for 435–444 (2005). Neurol. 12 (Suppl. 1), S2–S9 (1997). the classification of transport proteins. J. Cell 209. The Retinoids. Biology, Chemistry and Medicine 235. Southam, E. et al. Effect of lamotrigine on the Biochem. Suppl. 32–33, 84–94 (1999). (eds Mangelsdorf, D. J. et al.) 319–349 (Raven Press, activities of monoamine oxidases A and B in vitro and 259. Owens, M. J., Morgan, W. N., Plott, S. J. & New York, 1994). on monoamine disposition in vivo. Eur. J. Pharmacol. Nemeroff, C. B. Neurotransmitter receptor and 210. Czernielewski, J., Michel, S., Bouclier, M., Baker, M. 519, 237–245 (2005). transporter binding profile of antidepressants and & Hensby, J. C. Adapalene biochemistry and the 236. Lou, B. S., Lin, T. H. & Lo, C. Z. The interactions of their metabolites. J. Pharmacol. Exp. Ther. 283, evolution of a new topical retinoid for treatment of phenytoin and its binding site in DI-S6 segment of Na+ 1305–1322 (1997). acne. J. Eur. Acad. Dermatol. Venereol. 15 (Suppl 3), channel voltage-gated peptide by NMR spectroscopy 260. Blakely, R. D., De Felice, L. J. & Hartzell, H. C. 5–12 (2001). and molecular modeling study. J. Pept. Res. 66, Molecular physiology of norepinephrine and serotonin 211. Duriez, P. Mechanism of actions of statins and 27–38 (2005). transporters. J. Exp. Biol. 196, 263–281 (1994). fibrates. Therapie 58, 5–14 (2003). 237. Faber, T. S. & Camm, A. J. The differentiation of 261. Bondarev, M. L., Bondareva, T. S., Young, R. & 212. Staels, B. et al. Mechanism of action of fibrates on propafenone from other class Ic agents, focusing on Glennon, R. A. Behavioral and biochemical lipid and lipoprotein metabolism. Circulation 98, the effect on ventricular response rate attributable to investigations of bupropion metabolites. Eur. J. 2088–2093 (1998). its beta-blocking action. Eur. J. Clin. Pharmacol. 51, Pharmacol. 474, 85–93 (2003). 213. Willson, T. M. et al. The structure–activity relationship 199–208 (1996). 262. Beique, J. C., Lavoie, N., de Montigny, C. & Debonnel, between peroxisome proliferator-activated receptor 238. White, H. S. Molecular pharmacology of topiramate: G. Affinities of venlafaxine and various reuptake agonism and the antihyperglycemic activity of managing seizures and preventing migraine. inhibitors for the serotonin and norepinephrine thiazolidinediones. J. Med. Chem. 39, 665–668 Headache 45 (Suppl. 1), S48–S56 (2005). transporters. Eur. J. Pharmacol. 349, 129–132 (1996). 239. Gurvich, N. & Klein, P. S. Lithium and valproic acid: (1998). 214. Brent, G. A. The molecular basis of thyroid hormone parallels and contrasts in diverse signaling contexts. 263. Henry, J. P. et al. Biochemistry and molecular biology action. N. Engl. J. Med. 331, 847–853 (1994). Pharmacol. Ther. 96, 45–66 (2002). of the vesicular monoamine transporter from 215. Saier Lab Bioinformatics Group. Transport 240. Kang, M., Lisk, G., Hollingworth, S., Baylor, S. M. & chromaffin granules. J. Exp. Biol. 196, 251–262 Classification Database [online],
NATURE REVIEWS | DRUG DISCOVERY VOLUME 5 | OCTOBER 2006 | 833 PERSPECTIVES
280. Hermann, T. Drugs targeting the ribosome. Curr. Opin. 289. Davis, L. A. Omalizumab: a novel therapy for allergic 298. Bain, B. & Brazil, M. Adalimumab. Nature Rev. Drug Struct. Biol. 15, 355–366 (2005). asthma. Ann. Pharmacother. 38, 1236–1242 Discov. 2, 693–694 (2003). 281. Anokhina, M. M., Barta, A., Nierhaus, K. H., (2004). 299. Winterfield, L. S. & Menter, A. Infliximab. Dermatol. Spiridonova, V. A. & Kopylov, A. M. Mapping of the 290. Hooks, M. A., Wade, C. S. & Millikan, W. J., Jr. Ther. 17, 409–426 (2004). second tetracycline binding site on the ribosomal Muromonab CD-3: a review of its pharmacology, 300. Faulds, D. & Sorkin, E. M. Abciximab (c7E3 Fab). small subunit of E. coli. Nucleic Acids Res. 32, pharmacokinetics, and clinical use in transplantation. A review of its pharmacology and therapeutic potential 2594–2597 (2004). Pharmacotherapy 11, 26–37 (1991). in ischaemic heart disease. Drugs 48, 583–598 282. Spizek, J., Novotna, J. & Rezanka, T. Lincosamides: 291. Witzig, T. E. Yttrium-90-ibritumomab tiuxetan (1994). chemical structure, biosynthesis, mechanism of action, radioimmunotherapy: a new treatment approach for 301. Noseworthy, J. H. & Kirkpatrick, P. Natalizumab. resistance, and applications. Adv. Appl. Microbiol. 56, B-cell non-Hodgkin’s lymphoma. Drugs Today (Barc.) Nature Rev. Drug Discov. 4, 101–102 (2005). 121–154 (2004). 40, 111–119 (2004). 283. Harms, J. M., Schlunzen, F., Fucini, P., Bartels, H. & 292. Multani, P. & White, C. A. Rituximab. Cancer Acknowledgements Yonath, A. Alterations at the peptidyl transferase Chemother. Biol. Response Modif. 21, 235–258 We thank the following colleagues for help with compiling the centre of the ribosome induced by the synergistic (2003). first draft: T. Buβ, L. Ann Bailey, H. Morck, M. Ramadan and action of the streptogramins dalfopristin and 293. Linenberger, M. L. CD33-directed therapy with T. Rogosch (Fachbereich Pharmazie, Universität Marburg, quinupristin. BMC Biol. 2, 4 (2004). gemtuzumab ozogamicin in acute myeloid leukemia: Germany), and C. Oehler and R. Schneider (Institut für 284. Nygren, P., Sorbye, H., Osterlund, P. & Pfeiffer, P. progress in understanding cytotoxicity and potential Pharmazie, Universität Halle, Germany). targeted drugs in metastatic colorectal cancer with mechanisms of drug resistance. Leukemia 19, special emphasis on guidelines for the use of bevacizu- 176–182 (2005). Competing interests statement mab and cetuximab. Acta Oncol. 44, 203–217 (2005). 294. Frampton, J. E. & Wagstaff, A. J. Alemtuzumab. Drugs The authors declare no competing financial interests. 285. Muhsin, M., Graham, J. & Kirkpatrick, P. Bevacizumab. 63, 1229–1243 (2003). Nature Rev. Drug Discov. 3, 995–996 (2004). 295. Scott, L. J. & Lamb, H. M. Palivizumab. Drugs 58, 286. Marecki, S. & Kirkpatrick, P. Efalizumab. Nature Rev. 305–313 (1999). FURTHER INFORMATION Drug Discov. 3, 473–474 (2004). 296. Kapic, E., Becic, F. & Kusturica, J. Basiliximab, PDSP Ki Database: http://kidb.case.edu 287. Goldberg, R. M. Cetuximab. Nature Rev. Drug Discov. mechanism of action and pharmacological properties. Therapeutic Target Database: 4, S10–S11 (2005). Med. Arh. 58, 373–376 (2004). http://xin.cz3.nus.edu.sg/group/cjttd/ttd.asp 288. Albanell, J., Codony, J., Rovira, A., Mellado, B. & 297. Carswell, C. I., Plosker, G. L. & Wagstaff, A. J. WHO Collaborating Centre for Drug Statistics Methodology: Gascon, P. Mechanism of action of anti-HER2 monoclonal Daclizumab: a review of its use in the management of http://www.whocc.no/atcddd/ antibodies: scientific update on trastuzumab and 2C4. organ transplantation. BioDrugs 15, 745–773 Access to this interactive links box is free online. Adv. Exp. Med. Biol. 532, 253–268 (2003). (2001).
834 | OCTOBER 2006 | VOLUME 5 www.nature.com/reviews/drugdisc