Targets for Drug Action (2)

8/3/2019 Targets for Drug Action (2)

1/22

TARGETS OF DRUG ACTION

BY

ABDUL KHADER MOHAMMADM.PHARMACY(PHARMACOLOGY)

1ST SEMISTERSIMS COLLEGE OF PHARMACY

1


2/22

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.

2


3/22

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

3


4/22

DRUG:

RECEPTORS:

ION CHANNELS:

ENZYMES:

TRANSPORT PROTEINS:

4


5/22

5


6/22

RECEPTORS RECEPTORS:sensing elements in the system of chemical

communication,w

hich co-ordinates functions of all differentcells in body.

TYPES OF RECEPTORS:

6


7/22

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.

7


8/22


9/22

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.

9


10/22

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

10


11/22

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.

11


12/22

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.

12


13/22

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.

13


14/22

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,

14


15/22

Drugs can produce effects on enzyme reactions by substrate competition or by

reversibly or irreversibly modifying the enzyme.

ENZYMES

15


16/22

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.

16


17/22

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):

17


18/22

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.

18


19/22

Ion channels Blockers Modulators

Voltage-gated NA+

channels

Local anesthetics Veratridine

Voltage gated Ca+channels

Divalent cations (cd+2) dihydropyridine

19


20/22

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

20


21/22

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.

21


22/22

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.

22

Targets for Drug Action (2)

Documents

Transcript of Targets for Drug Action (2)