DRUG AND DRUG TARGET

DRUGS AND DRUG TARGETS

What is a drug target? And how many such targets are there? Here, we consider the nature of drug targets, and by classifying known drug substances on the basis of the discussed principles we provide an estimation of the total number of current drug targets.

Estimations of the total number of drug targets are presently dominated by analyses of the human genome, which are limited for various reasons, including the inability to infer the existence of splice variants or interactions between the encoded proteins from gene sequences alone, and the fact that the function of most of the DNA in the genome remains unclear. In 1997, when 100,000 protein-coding sequences were hypothesized to exist in the human genome, Drews and Ryser estimated the number of molecular targets 'hit' by all marketed drug substances to be only 482 .In 2002, after the sequencing of the human genome, others arrived at 8,000 targets of pharmacological interest, of which nearly 5,000 could be potentially hit by traditional drug substances, nearly 2,400 by antibodies and 800 by protein pharmaceuticals. And on the basis of ligand-binding studies, 399 molecular targets were identified belonging to 130 protein families, and 3,000 targets for small-molecule drugs were predicted to exist by extrapolations from the number of currently identified such targets in the human genome.

In summary, current target counts are of the order of 10², whereas estimations of the number of potential drug targets are an order of magnitude higher. In this paper, we consider the nature of drug targets, and use a classification based on this consideration, and a list of approved drug substances to estimate the number of known drug targets, in the following categories:

Table 1 | Enzymes

Type	Activity of drug	Drug examples
Oxidoreductases
Aldehyde dehydrogenase	Inhibitor	Disulfiram
Monoamine oxidases (MAOs)	MAO-A inhibitor	Tranylcypromine, moclobemide
	MAO-B inhibitor	Tranylcypromine
Cyclooxygenases (COXs)	COX1 inhibitor	Acetylsalicylic acid, profens, acetaminophen and dipyrone (as arachidonylamides)
	COX2 inhibitor	Acetylsalicylic acid, profens, acetaminophen and dipyrone (as arachidonylamides)
Vitamin K epoxide reductase	Inhibitor	Warfarin, phenprocoumon
Aromatase	Inhibitor	Exemestane
Lanosterol demethylase (fungal)	Inhibitor	Azole antifungals
Lipoxygenases	Inhibitor	Mesalazine
	5-lipoxygenase inhibitor	Zileuton
Thyroidal peroxidase	Inhibitor	Thiouracils
Iodothyronine-5' deiodinase	Inhibitor	Propylthiouracil
Inosine monophosphate dehydrogenase	Inhibitor	Mycophenolate mofetil
HMG-CoA reductase	Inhibitor	Statins
5 -Testosterone reductase	Inhibitor	Finasteride, dutasteride
Dihydrofolate reductase (bacterial)	Inhibitor	Trimethoprim
Dihydrofolate reductase (human)	Inhibitor	Methotrexate, pemetrexed
Dihydrofolate reductase (parasitic)	Inhibitor	Proguanil
Dihydroorotate reductase	Inhibitor	Leflunomide
Enoyl reductase (mycobacterial)	Inhibitor	Isoniazid
Squalene epoxidase (fungal)	Inhibitor	Terbinafin
14 reductase (fungal)	Inhibitor	Amorolfin
Xanthine oxidase	Inhibitor	Allopurinol
4-Hydroxyphenylpyruvate dioxygenase	Inhibitor	Nitisinone
Ribonucleoside diphosphate reductase	Inhibitor	Hydroxycarbamide
Transferases
Protein kinase C	Inhibitor	Miltefosine
Bacterial peptidyl transferase	Inhibitor	Chloramphenicol
Catecholamine-O-methyltransferase	Inhibitor	Entacapone
RNA polymerase (bacterial)	Inhibitor	Ansamycins
Reverse transcriptases (viral)	Competitive inhibitors	Zidovudine
	Allosteric inhibitors	Efavirenz
DNA polymerases	Inhibitor	Acyclovir, suramin
GABA transaminase	Inhibitor	Valproic acid vigabatrin
Tyrosine kinases	PDGFR/ABL/KIT inhibitor	Imatinib
	EGFR inhibitor	Erlotinib
	VEGFR2/PDGFR /KIT/FLT3	Sunitinib
	VEGFR2/PDGFR /RAF	Sorafenib
Glycinamide ribonucleotide formyl transferase	Inhibitor	Pemetrexed
Phosphoenolpyruvate transferase (MurA, bacterial)	Inhibitor	Fosfomycin
Human cytosolic branched-chain aminotransferase (hBCATc)	Inhibitor	Gabapentin
Hydrolases (proteases)
Aspartyl proteases (viral)	HIV protease inhibitor	Saquinavir, indinavir
Hydrolases (serine proteases)
Unspecific	Unspecific inhibitors	Aprotinine
Bacterial serine protease	Direct inhibitor	-lactams
Bacterial serine protease	Indirect inhibitor	Glycopeptides
Bacterial lactamases	Direct inhibitor	Sulbactam
Human antithrombin	Activator	Heparins
Human plasminogen	Activator	Streptokinase
Human coagulation factor	Activator	Factor IX complex, Factor VIII
Human factor Xa	Inhibitor	Fondaparinux
Hydrolases (metalloproteases)
Human ACE	Inhibitor	Captopril
Human HRD	Inhibitor	Cilastatin
Human carboxypeptidase A (Zn)	Inhibitor	Penicillamine
Human enkephalinase	Inhibitor	Racecadotril
Hydrolases (other)
26S proteasome	Inhibitor	Bortezomib
Esterases	AChE inhibitor	Physostigmine
	AChE reactivators	Obidoxime
	PDE inhibitor	Caffeine
	PDE3 inhibitor	Amrinon, milrinone
	PDE4 inhibitor	Papaverine
	PDE5 inhibitor	Sildenafil
	HDAC inhibitor	Valproic acid
	HDAC3/HDAC7 inhibitor	Carbamezepine
Glycosidases (viral)	-glycosidase inhibitor	Zanamivir, oseltamivir
Glycosidases (human)	-glycosidase inhibitor	Acarbose
Lipases	Gastrointestinal lipases inhibitor	Orlistat
Phosphatases	Calcineurin inhibitor	Cyclosporin
	Inositol polyphosphate phosphatase inhibitor	Lithium ions
GTPases	Rac1 inhibitor	6-Thio-GTP (azathioprine metabolite)
Phosphorylases	Bacterial C55-lipid phosphate dephosphorylase inhibitor	Bacitracin
Lyases
DOPA decarboxylase	Inhibitor	Carbidopa
Carbonic anhydrase	Inhibitor	Acetazolamide
Histidine decarboxylase	Inhibitor	Tritoqualine
Ornithine decarboxylase	Inhibitor	Eflornithine
Soluble guanylyl cyclase	Activator	Nitric acid esters, molsidomine
Isomerases
Alanine racemase	Inhibitor	D-Cycloserine
DNA gyrases (bacterial)	Inhibitor	Fluoroquinolones
Topoisomerases	Topoisomerase I inhibitor	Irinotecan
	Topoisomerase II inhibitor	Etoposide
8,7 isomerase (fungal)	Inhibitor	Amorolfin
Ligases (also known as synthases)
Dihydropteroate synthase	Inhibitor	Sulphonamides
Thymidylate synthase (fungal and human)	Inhibitor	Fluorouracil
Thymidylate synthase (human)	Inhibitor	Methotrexate, pemetrexed
Phosphofructokinase	Inhibitor	Antimony compounds
mTOR	Inhibitor	Rapamycin
Haem polymerase (Plasmodium)	Inhibitor	Quinoline antimalarials
1,3- -D-glucansynthase (fungi)	Inhibitor	Caspofungin
Glucosylceramide synthase	Inhibitor	Miglustat

TABLE 2 | Receptors

Type	Activity of drug	Drug examples
Direct ligand-gated ion channel receptors
GABAA receptors	Barbiturate binding site agonists	Barbiturate
	Benzodiazepine binding site agonists	Benzodiazepines
	Benzodiazepine binding site antagonists	Flumazenil
Acetylcholine receptors	Nicotinic receptor agonists	Pyrantel (of Angiostrongylus), levamisole
	Nicotinic receptor stabilizing antagonists	Alcuronium
	Nicotinic receptor depolarizing antagonists	Suxamethonium
	Nicotinic receptor allosteric modulators	Galantamine
Glutamate receptors (ionotropic)	NMDA subtype antagonists	Memantine
	NMDA subtype expression modulators	Acamprosate
	NMDA subtype phencyclidine binding site antagonists	Ketamine
G-protein-coupled receptors
Acetylcholine receptors	Muscarinic receptor agonists	Pilocarpine
	Muscarinic receptor antagonists	Tropane derivatives
	Muscarinic receptor M3 antagonists	Darifenacine
Adenosine receptors	Agonists	Adenosine
	Adenosine A1 receptor agonists	Lignans from valerian
	Adenosine A1receptor antagonists	Caffeine, theophylline
	Adenosine A2A receptor antagonists	Caffeine, theophylline
Adrenoceptors	Agonists	Adrenaline, noradrenaline, ephedrine
	1- and 2-receptors agonists	Xylometazoline
	1-receptor antagonists	Ergotamine
	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	Sartans
Calcium-sensing receptor	Agonists	Strontium ions
	Allosteric activators	Cinacalcet
Cannabinoid receptors	CB1 - and CB2-receptors agonists	Dronabinol
Cysteinyl-leukotriene receptors	Antagonists	Montelukast
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
Endothelin receptors (ETA, ETB)	Antagonists	Bosentan
GABAB receptors	Agonists	Baclofen
Glucagon receptors	Agonists	Glucagon
Glucagon-like peptide-1 receptor	Agonists	Exenatide
Histamine receptors	H1-antagonists	Diphenhydramine
	H2-antagonists	Cimetidine
Opioid receptors173, 174	-opioid agonists	Morphine, buprenorphine
	-, - and -opioid antagonists	Naltrexone
	-opioid antagonists	Buprenorphine
Neurokinin receptors	NK1 receptor antagonists	Aprepitant
Prostanoid receptors	Agonists	Misoprostol, sulprostone, iloprost
Prostamide receptors	Agonists	Bimatoprost
Purinergic receptors	P2Y12 antagonists	Clopidogrel
Serotonin receptors	Subtype-specific (partial) agonists	Ergometrine, ergotamine
	5-HT1A partial agonists	Buspirone
	5-HT1B/1D agonists	Triptans
	5-HT2A antagonists	Quetiapine, ziprasidone
	5-HT3 antagonists	Granisetron
	5-HT4 partial agonists	Tegaserode
Vasopressin receptors184	Agonists	Vasopressin
	V1 agonists	Terlipressin
	V2 agonists	Desmopressin
	OT agonists	Oxytocin
	OT antagonists	Atosiban
Cytokine receptors
Class I cytokine receptors	Growth hormone receptor antagonists	Pegvisomant
	Erythropoietin receptor agonists	Erythropoietin
	Granulocyte colony stimulating factor agonists	Filgrastim
	Granulocyte-macrophage colony stimulating factor agonists	Molgramostim
	Interleukin-1 receptor antagonists	Anakinra
	Interleukin-2 receptor agonists	Aldesleukin
TNF receptors	Mimetics (soluble)	Etanercept
Integrin receptors
Glycoprotein IIb/IIIa receptor	Antagonists	Tirofiban
Receptors associated with a tyrosine kinase
Insulin receptor	Direct agonists	Insulin
Insulin receptor	Sensitizers	Biguanides
Nuclear receptors (steroid hormone receptors)
Mineralocorticoid receptor196	Agonists	Aldosterone
	Antagonists	Spironolactone
Glucocorticoid receptor	Agonists	Glucocorticoids
Progesterone receptor	Agonists	Gestagens
Oestrogen receptor199	Agonists	Oestrogens
	(Partial) antagonists	Clomifene
	Antagonists	Fulvestrant
	Modulators	Tamoxifen, raloxifene
	Androgen receptor201, 202 Agonists	Testosterone
	Antagonists	Cyproterone acetate
Vitamin D receptor205, 206	Agonists	Retinoids
ACTH receptor agonists	Agonists	Tetracosactide (also known as cosyntropin)
Nuclear receptors (other)
	Retinoic acid receptors RAR agonists	Isotretinoin
	RAR agonists	Adapalene, isotretinoin
	RAR agonists	Adapalene, isotretinoin
Peroxisome proliferator-activated receptor (PPAR)	PPAR agonists	Fibrates
	PPAR agonists	Glitazones
Thyroid hormone receptors	Agonists	L-Thyroxine

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TABLE 3 | Ion channels

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Type	Activity of drug	Drug examples
Voltage-gated Ca2+ channels
General	Inhibitor	Oxcarbazepine
In Schistosoma sp.	Inhibitor	Praziquantel
L-type channels	Inhibitor	Dihydropyridines, diltiazem, lercanidipine, pregabalin, verapamil
T-type channels	Inhibitor	Succinimides
K+ channels225
Epithelial K+ channels	Opener Inhibitor	Diazoxide, minoxidilNateglinide, sulphonylureas
Voltage-gated K+ channels	Inhibitor	Amiodarone
Na+ channels
Epithelial Na+ channels (ENaC)231	Inhibitor	Amiloride, bupivacaine, lidocaine, procainamide, quinidine
Voltage-gated Na+ channels	Inhibitor	Carbamazepine, flecainide, lamotrigine, phenytoin, propafenone, topiramate, valproic acid,
Ryanodine-inositol 1,4,5-triphosphate receptor Ca2+ channel (RIR-CaC) family
Ryanodine receptors	Inhibitor	Dantrolene
Transient receptor potential Ca2+ channel (TRP-CC) family
TRPV1 receptors	Inhibitor	Acetaminophen (as arachidonylamide)
Cl- channels243
Cl-channel	Inhibitor (mast cells) Opener (parasites)	Cromolyn sodium Ivermectin

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TABLE 4 | Transport proteins (uniporters, symporters and antiporters)

Type	Activity of drug	Drug examples
Cation-chloride cotransporter (CCC) family247	Thiazide-sensitive NaCl symporter, human inhibitor	Thiazide diuretics
	Bumetanide-sensitive NaCl/KCl symporters, human inhibitor	Furosemide
Na+/H+ antiporters	Inhibitor	Amiloride, triamterene
Proton pumps	Ca2+-dependent ATPase (PfATP6; Plasmodia) inhibitor	Artemisinin and derivatives
H+/K+-ATPase	Inhibitor	Omeprazole
Na+/K+ ATPase	Inhibitor	Cardiac glycosides
Eukaryotic (putative) sterol transporter (EST) family	Niemann-Pick C1 like 1 (NPC1L1) protein inhibitor	Ezetimibe
Neurotransmitter/Na+ symporter (NSS) family257, 258	Serotonin/Na+ symporter inhibitor	Cocaine, tricyclic antidepressants, paroxetine
	Noradrenaline/Na+ symporter inhibitor	Bupropion, venlafaxine
	Dopamine/Na+ symporter inhibitor	Tricyclic antidepressants, cocaine, amphetamines
	Vesicular monoamine transporter inhibitor	Reserpine

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TABLE 5 | DNA/RNA and the ribosome

Target	Activity of drug	Example drugs
Nucleic acids
DNA and RNA265	Alkylation	Chlorambucil, cyclophosphamide, dacarbazine
	Complexation	Cisplatin
	Intercalation	Doxorubicin
	Oxidative degradation	Bleomycin
	Strand breaks	Nitroimidazoles
RNA	Interaction with 16S-rRNA	Aminoglycoside antiinfectives
	Interaction with 23S-rRNA	Macrolide antiinfectives
	23S-rRNA/tRNA/2-polypeptide complex	Oxazolidinone antiinfectives
Spindle	Inhibition of development	Vinca alkaloids
	Inhibition of desaggregation	Taxanes
Inhibition of mitosis	—	Colchicine
Ribosome
30S subunit (bacterial)	Inhibitors	Tetracyclines
50S subunit (bacterial)	Inhibitors	Lincosamides, quinupristin– dalfopristin282, 283

TABLE 6 | Targets of monoclonal antibodies

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Target	Agent
Vascular endothelial growth factor	Bevacizumab
Lymphocyte function-associated antigen 1	Efalizumab
Epidermal growth factor receptor	Cetuximab
Human epidermal growth factor receptor 2	Trastuzumab
Immunoglobulin E (IgE)	Omalizumab
CD-3	Muromonab-CD3
CD-20	Rituximab, ibritumomab tiuxetan, 131I-tositumomab
CD-33	Gemtuzumab
CD-52	Alemtuzumab
F protein of RSV subtypes A and B	Palivizumab
CD-25	Basiliximab, daclizumab
Tumour-necrosis factor-	Adalimumab, infliximab
Glycoprotein IIb/IIIa receptor	Abciximab
4-Integrin subunit	Natalizumab

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TABLE 7 | Various physicochemical mechanisms

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Mechanism	Agent
Ion exchange	Fluoride
Acid binding	Magnesium hydroxide, aluminium hydroxide
Adsorptive	Charcoal, colestyramine
Adstringent	Bismuth compounds
Surface-active	Simeticone, chlorhexidine, chloroxylene
Surface-active on cell membranes	Coal tar
Surface-active from fungi	Nystatin, amphotericin B
Mucosal irritation	Anthrones, anthraquinones
Osmotically active	Lactulose, dextran 70, polygeline, glucose, electrolyte solutions, mannitol
Water binding	Urea, ethanol
UV absorbant	4-Aminobenzoic acid derivatives
Reflective	Zinc oxide, titanium dioxide
Oxidative	Tannines, polyphenoles, dithranol, polyvidon iodide, silver nitrate, hypochlorite, permanganate, benzoylperoxide, nitroimidazoles, nitrofuranes, temoporfin (mainly via singlet oxygen, cytostatic drug), verteporfin (mainly via singlet oxygen, ophthalmic drug)
Reduce disulphide bridges	D-Penicillamine, N-acetyl-cysteine
Complexing agents	Al3+, arsenic compounds
Salt formation	Sevelamer
Modification of tertiary structure	Enfuvirtide (from HIV glycoprotein 41)