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TARGETS OF DRUG ACTION
BY
ABDUL KHADER MOHAMMADM.PHARMACY(PHARMACOLOGY)
1ST SEMISTERSIMS COLLEGE OF PHARMACY
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VARIOUS TARGETS OF DRUG ACTION
TARGETS:
naturally exisiting cellular ormolecular structure involoved in thepathology of interest that the drug indevelopment is meant to act on.
RECEPTORS
ION CHANNELS
ENZYMES
TRANSPORTERS
Exceptions:
1. Colchicinewhich interacts with
Tubulin protein.2. Ciclosporin which binds to cytosolic
proteins known as Immunophilins.
3. Chemotherapeutic drugs which actswith DNA and Cell wall constituents.
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In 2006, Imming et al. catalogued218 molecular targets for
approved drug substances, whereas Zheng et al. disclose 268
successful targets in the current version of the Therapeutic
Targets Database.
Currently therapy is based upon less than 500molecular
targets:
45%ofwhich are G-protein coupled receptors
28%are enzymes
11%are hormones and factors
5% ion channels
2% nuclear receptors
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DRUG:
RECEPTORS:
ION CHANNELS:
ENZYMES:
TRANSPORT PROTEINS:
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RECEPTORS RECEPTORS:sensing elements in the system of chemical
communication,w
hich co-ordinates functions of all differentcells in body.
TYPES OF RECEPTORS:
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LIGAND GATED ION CHANNELS
Also known as ionotropic receptors.
These are the receptors on which fast
neurotransmitters act.
Examples : nicotinic acetylcholine (nAChR);
GABAA receptor and glutamate receptors ofNMDA, AMPA and kainate types.
LOCATION: membrane
EFFECTOR: ion channel
COUPLING: direct
STRUCTURE: oligomeric assembly of subunits
surrounding central pore.
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G-protein coupled receptors (GPCRs)
Also known as metabotropic receptors or 7-transmembrane receptors.
Exs: muscarnic acetylcholine receptor(mAChR); adrenoreceptors, and chemokinereceptors.
LOCATION: membrane
EFFECTOR: channel or enzyme
COUPLING: G-protein
STRUCTURE: mono or oligomeric assembly
of subunits comprising 7 transmembranehelices with intracellular G-protein coupling
domain.
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Targets for G-proteins Main targets for G-proteins through which GPCRs control
various aspects of cell functions are:
1. Adenylyl cyclase
2. Phospholipase C
3. Ion channels
4. Rho A/Rho Kinase
5. Mitogen-activated protein Kinase
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Kinase-linked receptors
Heterogenous group of membranereceptors responding mainly to
protein mediators.
Exs: insulin, growth factors, cytokine
receptors.
LOCATION: membrane
EFFECTOR: protein kinases
COUPLING: direct
STRUCTURE: single transmembrane
helix linking extracellular receptor
domain to intracellular
kinase domain.
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3 Types:
1. Receptor tyrosinekinases(RTKs): receptorsincorporate a tyrosine kinasemoiety in the intracellularregion. Eg:growth factors(epidermal and nerve); Insulinreceptors;
2. Serine/threonine kinases:similar in structure to RTKs butphosphorylate serine orthreonine residues rather thantyrosine. Eg:Transforminggrowth factor (TGF);
3. Cytokine receptors: lackintrinsic enzyme activity.
they associate with, andactivate, a cytosolic tyrosinekinase, such as Jak or otherkinases. Eg:interferons,colony-stimulating factors.
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Nuclear Receptors
Nuclear receptor term is a
misnomer because some are
actually located in the cytosol and
migrate to nuclear compartment
when a ligand is present.
LOCATION: intracellular EFFECTOR: gene transcription
COUPLING: Via DNA
STRUCTURE: monomeric structure
with separate receptor and DNA-binding domains.
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A family of 48 soluble receptors that senselipid and hormone signals and modulate genetranscription.
Responsible for biological effects of approx10% of prescription drugs.
Involved in endocrine signaling;
Malfunctions:inflammation, cancer,diabetes, obesity, cardiovascular disorders
and reproductive disorders. 2 main classes:
Class 1: present in the cytoplasm, formhomodiamers in the presence of their partner,and migrate to nucleus. ligands are endocrinein nature. Eg: steroid hormones.
Class 2: generally present in the nucleus,forms heterodiamers with retinoid X receptor.ligands are usually lipids. Eg: fatty acids.
A 3rd subgroup transduces mainly endocrinesignals but functions as heterodiamers.
Eg:
thyroid hormone.
Class 1
Cytoplasm
Homodiamers
Endocrine ligands
High affinity
Eg: GR, MR, ER, PR
Class 2
Nucleus
Heterodiamers
Lipid ligands
Low affinity
Eg: PPAR, LXR,RXR
Hybrid classEndocrine ligands
RXR hetero diamers
Eg: thyroid receptors,
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Drugs can produce effects on enzyme reactions by substrate competition or by
reversibly or irreversibly modifying the enzyme.
ENZYMES
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TRANSPORTERS
Many epithelia (eg: renal tubules,exocrine glands) are specialized totransport specific ions.
This transport depends on aspecial class of epithelial sodiumchannels (ENaCs).
ENaCs allow Na+ entry into cell atone surface, couple to activate
extrusion of Na+ or exchange ofanother ion, from the oppositesurface.
Anion channel depends upon aspecific chloride channel,mutations ofwhich result in cysticfibrosis.
These activities are regulated byvarious second messengers, whichcontrol the transport of ions inspecific ways.
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Transport proteins Inhibitors False substrates
Noradrenaline
transporter
Tricyclic anti-
depressants,Cocaine.
Amphetamine,
Methyldopa
Weak acid carrier
(renal tubule)
Probenecid
Na+/K+/2Cl- transporter Loop diuretics
Proton pump Omeprazole
The main transporters involved in drug action are symporters and
antiporters (exchangers):
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Ion channels
Voltage-gated channels:
Channels open when cell membrane isdepolarized
mechanism: membrane excitability.
Sodium, potassium, calcium channels
Channel opening is short lasting;
Ligand-gated channels: Activate by binding of a chemical ligand
to a site on the channel molecule.
Fast neurotransmitters eg:glutamate,acetylcholine, GABA and ATP acts bybinding to sites outside of themembrane.
Some ligand gated channels in plasmamembrane respond to intracellularsignals. Eg:calcium-activatedpotassium channels,
ATP-sensitive potassium channels.
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Ion channels Blockers Modulators
Voltage-gated NA+
channels
Local anesthetics Veratridine
Voltage gated Ca+channels
Divalent cations (cd+2) dihydropyridine
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Besides classical methods of cellular and molecular biology, new techniques
of target identification are becoming increasingly important. These include:
a) Genomics
b) Bioinformatics
c) Proteomicsa) Genomics: evolved from 2 independent advances:
1) Automation resulting in a significant increase in the number of experimentsthat could be constructed in a given time. (eg. DNA sequencing)
2) Informatics- the ability to transform raw data into meaningful information byapplying computerized techniques for managing, analyzing, and interpreting data.
b) Bioinformatics the in silico identification of novel drug targets is nowfeasible by systematically searching for paralogs (related proteins within an
organism) of known drug targets (eg. may be able to modify an existing drug to
bind to the paralog).
c) Proteomics concerning expression analysis, it has been shown that thecorrelation between RNA and protein expression is weak and ranges in yeast from
10-40% for lower abundance proteins to up to 94% for higher abundance proteins.
Modern methods for target identification
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CONCLUSION
The process of drug discovery starts with the identification of a potentialtarget at which the drug can act. The target can be an enzyme in a vital
pathway, a receptor, a transporter, a protein in signal transduction or any
protein produced in a pathological condition.
At an early stage, the targets can be characterised based on
pharmacogenetic studies combinedw
ith proteomics and suitable drugcompounds selected.
These current new concepts are making only a betterment for the present
study and thereby for the control of diseases to make it fruitful for the
survival of human beings.
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REFERENCES
RANG AND DALES PHARMACOLOGY 7TH EDITION.
JOURNAL DRUG DISCOVERY TODAY:FINDING NEW DRUG TAREGTS IN THE
21ST CENTURY by MARK A.LINDSAY. VOLUME 10/NUMBER
23/24/DECEMBER 2005/PAGE 1683
JOURNAL DRUG DISCOVERY TODAY:TARGET BASED DRUG DISCOVERY:ISSOMETHING WRONG? VOLUME10/NUMBER 2/JANUARY 2005/PAGE 139
JOURNAL DRUG DISCOVERY:HOW MANY DRUG TARGETS ARE THERE?
VOLUME:5,DECEMBER 2006, PAGE 994.
JOURNAL DRUG DISCOVERY:DRUGS,THEIR TARGETSAND THE NATURE
AND NUMBER OF DRUG TARGETS VOLUME 5/OCTOBER 2006/PAGE 821 Journal:Molecular aspects of drug action.
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