126999554 drug receptor bonding signal transduction 05mars2012 10

7/29/2019 126999554 Drug Receptor Bonding Signal Transduction 05mars2012 10

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Drug-Receptor bonding &

signal transduction

Dr V.N NDIKUM

8-Mar-12


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Characteristics of a Receptors

Specificity Receptor interacts with one type of ligand or a structurally related family

ofligands

Competition between related ligands Example: glucose transporter binds D-glucose specif ically

Affinity Energetics of ligand receptor interactions

Energetics of binding determine specificity Intrinsic activity

A measure of the ability of a bound drug to activate the receptor Distinguishes agonist from antagonist

Saturability Finite number of binding sites on a receptor, along with specificity of

interactions, implies that binding sites can become fully occupied withligand molecules Additionalligand leads to non-specific binding


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Molecular Level of Drug-receptor interaction

Specificity of Molecular Level Recognition :

Protein receptors have specific three dimensionalstructure

Generally, receptor binding sites are regions ofthe protein with a specific arrangement ofcharged amino acid side chains that are exposed,allowing access to the binding molecule (drug)

Site must be spatially and energetically favorablefor binding

Binding of ligand to receptor can lead toconformational changes making further bindingmore favorable


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Types of Chemical Bonds in Ligand-Receptor Interactions

Affinity and Specificity based onchemical bonds

Covalent binding Ionic bonds (initial attraction)

Cation- interactions, hydrogen bonds

Vander Waals forces, hydrophobic

interactions


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Types of Bonding between & Receptors

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Types of receptors

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Types of receptors

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>50 % of all prescribed drug

affects GPCRs


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Signal transduction

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1. enzyme linked(multiple actions)

2. ion channel linked

(speedy)

3. G protein linked

(amplifier)

4. nuclear (gene) linked(long lasting)


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1. G protein-linked

receptors

Structure:

Single polypeptide

chain threaded back

and forth resulting in 7

transmembrane

helices

Theres a G proteinattached to the

cytoplasmic side of the

membrane (functions as

a switch).

Signal transduction


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2. Tyrosine-kinase receptors

Structure:

Receptors exist as individual polypeptides

Each has an extracellular signal-binding site

An intracellular tail with a number of tyrosinesand a single helix spanning the membrane

Signal transduction


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3. Ion channel

receptors

Structure:

Protein pores

in the plasmamembrane

Signal transduction


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Signal transduction: Intracellular receptors

Not all signal receptors are located on theplasma membrane.

Some are proteins located in the cytoplasmor nucleus of target cells.

The signal molecule must be able topass through plasma membrane.

Examples:

Ni tr ic oxide (NO) Steroid

(e.g., estradiol, progesterone, testosterone) and thyroid hormones of

animals).

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Concept of second in molecular Signal transduction

The concept of Second messenger

Second Messenger


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Characteristics of Second Messengers

Small, nonprotein, water-solublemolecules or ions

Readily spread throughout the cell bydiffusion

Two most widely used second messengersare:

1. Cycle AMP

2. Calcium ions Ca2+

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Ad l C l AMP P i Ki A (PKA)


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Adenylate

CyclaseR1

R2

As

Gs Gi

Ai

GTPGDP

GTPGDP

PDEAMP cAMP

ATP-Mg++

Reg Reg

C

C

C

C

Protein

Protein-P

Protein Kinase A

(PKA)PKA

Adenylate Cyclase, cAMP, Protein Kinase A (PKA)

PDE - phosphodiesterase

AMP S d M S t


23/3423Katzung, Basic and Clinical Pharmacology, 2001, p. 124

cAMP Second Messenger System

Phospholipase C Inositol Trisphosphate (IP )


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R

Ca++

PKC

Ca++Endoplasmic Reticulum

Gq

PLC

Protein

Protein-P

A

DAG

IP3

PIP2

Phospholipase C, Inositol Trisphosphate (IP3),

Ca2+ and Diacylglycerol, Protein Kinase C (PKC)

PLC phospholipase C

PIP2 phosphatidylinositol bisphosphate

IP3 inositol trisphosphate

DAG diacylglycerol

PKC protein kinase C


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cGMP

NO

Ca++

GTP

GMP

Intracellular

Ca++ StoresCa++

Ca++

Arginine

+

Citrulline GTP

NO

PDE

Membrane Bound

Guanylate Cyclase

Soluble

Guanylate Cyclase

C.M.

Ion Channels

cGMP-Dependent PK

PDEase Activity

NO

Synthetase

Guanylate Cyclase, Nitric Oxide Synthase (NOS), cGMP,cGMP-dependent Protein Kinase (PKG) and Phosphodiesterase


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Second messengers

Calcium Ions (Ca2+) and InositolTrisphosphate

Calcium more widely used than cAMP

used in neurotransmitters, growth factors,some hormones

Increases in Ca2+ causes many possibleresponses such as:

Muscle cell contr action

Secretion of certain substance

Cell division

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Benefits of a signal-transduction

Two benefits of a signal-transductionpathway1. Signal amplification

2. Signal specificity

Signal amplification Proteins persist in active form long enough

to process numerous molecules ofsubstrate

Each catalytic step activates more productsthan in the proceeding steps

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Functional classification of

receptors

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System Type

acetylcholinergic acetylcholine nicotinic receptors

acetylcholine muscarinic receptorsmonoaminergic 1-adrenoceptors

2-adrenoceptors-adrenoceptorsdopamine receptors

serotonin receptor

aminoacidergic GABA receptors

glutamate ionotropic receptors

glutamate metabotropic receptors

glycine receptorshistamine receptors

peptidergic opioid receptors

other peptide receptors

purinergic adenosine receptors (P1

purinoceptors)

P2 purinoceptors

S bt f N i h i


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Subtypes of Norepinephrine

Receptors

RECEPTORS Subtype Transducer Structure(aa/TM)

1-adrenoceptors 1A Gq/11 IP3/DAG 466/7

1B

Gq/11

IP3/DAG 519/7

1D Gq/11 IP3/DAG 572/7

2-adrenoceptors 2A Gi/o cAMP 450/7

2B Gi/o cAMP 450/7

2C

Gi/o

cAMP 461/7

2D Gi/o cAMP 450/7

-adrenoceptors 1 Gs cAMP 477/7

2 Gs cAMP 413/7

3 Gs, Gi/o cAMP 408/7


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Subtypes of Dopamine Receptors

RECEPTORS Subtype Transducer Structure(aa/TM)

dopamine D1 Gs cAMP 446/7

D2 GiGq/11cAMPIP3/DAG, K

+,Ca2+

443/7

D3 Gi cAMP 400/7

D4 Gi cAMP, K+ 386/7

D5 Gs cAMP 477/7

S bt f S t i R t


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Subtypes of Serotonin ReceptorsRECEPTORS Subtype Transducer Structure

5-HT(5-hydroxytryptamine)

5-HT1A

Gi/o

cAMP 421/7

5-HT1B Gi/o cAMP 390/7

5-HT1D Gi/o cAMP 377/7

5-ht1E Gi/o cAMP 365/7

5-ht1F

Gi/o

cAMP 366/7

5-HT2A Gq/11 IP3/DAG 471/7

5-HT2B Gq/11 IP3/DAG 481/7

5-HT2C Gq/11 IP3/DAG 458/7

5-HT3

internal cationic channel 478

5-HT4 Gs cAMP 387/7

5-ht5A ? 357/7

5-ht5B ? 370/7

5-ht6 Gs cAMP 440/7

5-HT7 Gs cAMP 445/7


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126999554 drug receptor bonding signal transduction 05mars2012 10

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