DRUG-INDUCEDCONFORMATIONAL CHANGECONFORMATIONAL CHANGE

DR.DATTEN BANGUN MSc,SpFK , p&

DR.TRI WIDYAWATI.MSi

Bagian Farmakologi dan Terapeutik,Fakultas Kedokteran

Universitas Sumatera Utara

Pharmacology :

The st d of the manner in hich theThe study of the manner in which the function of living systems is affected by chemical agents.

Paul Ehrlich :Paul Ehrlich :

Struck by the high degree of chemical specificityfor the antiparasitic and toxic effect ofvarious synthetic organic chemical.

DrugDrug

• Chemical substance that affects theChemical substance that affects the functioning of living things

• May treat diagnose and prevent disease• May treat, diagnose, and prevent disease• Dates to ancient times• Over 9900 drugs available in U.S.

How drug act ?Paul Ehrlich :Paul Ehrlich :

Corpora non agunt nisi fixata

A drug will not work,unless it is boundunless it is bound

Kecuali : - osmotic diureticKecuali : - osmotic diuretic- osmotic purgatives- antasida- antasida- heavy metal chelating agents

Dengan apa berikatan ?

- Protein Molecules

- DNA * antimikroba

* anti neoplasma

Drug ReceptorDrug Receptor

• A macromolecular component of a cell with which a drug interacts tocell with which a drug interacts to produce a response

• Usually a protein• Usually a protein

ReceptorsMost drugs combine (bind) with specificreceptors to produce a particularp p presponse.This association or binding takes placeg pby precise:= physicochemical andp y= steric interactionsbetween specific groups of the drug andbetween specific groups of the drug andthe receptor.

Receptor ConformationReceptor Conformation

Drug-Receptor InteractionsgWhat factors influence binding?• Molecular structure

– Isomerism – Functional groups

Ri idit– Rigidity

• Peptide bond distance = 3 61angstroms• Peptide bond distance = 3.61angstroms– Drugs - spacial relationship between functional groups is typically a multiple of 3.61g p yp y p– Conformational changes in drugs occur to optimize this

Theory of Drug Action

Fi h ’ ‘L k d K ’ H th iFischer’s ‘Lock and Key’ Hypothesis

Every ‘lock’ has its own ‘key’If the ‘key’ is not precise, the ‘lock’ does not openThe ‘drug’ is the key that has to g yfit the target specifically and productively

o

Theory of Drug Action

Corollary of ‘Lock & Key’ HypothesisCorollary of ‘Lock & Key’ Hypothesis

OHCH3 CH3

OCH3

OHCHC

OH

OOH

OH OH

O

OOH O

O

CH2

CH2OH CH3

CH3 OH

O

N

CH3

CH3CH2CH3

Does not explain why some ‘keys’ open doors partially? e.g., partial agonists or partially? …… e.g., partial agonists or antagonists

Theory of Drug Action

K hl d’ ‘I d d Fit’ H th iKoshland’s ‘Induced-Fit’ Hypothesis

Hand & gloveHand & glove

At least two steps …… e.g., step 1 is initial binding and step 2 is a change in Con-initial binding and step 2 is a change in structure of the receptor (and/or drug)Receptor is flexible! …… can wrap around the drug …… the zipper model is extreme

Con-forma-tiong pp

case of induced-fitAll intermediate cases do exist in nature

change

Membrane effects on drug-receptorinteractionsinteractions

1.Structure of the receptor;a.protein,big enough ---p , g g

- hydrophilic domains reside in the intra andextracellular spaces

- lipophilic domain sit in the membraneb. small,only hydrophilic

domain- reside in the cytoplasm,nucleus or bothnucleus or both

Affects its ability to gain acces to the receptor:2.Structure of the drug;Affects its ability to gain acces to the receptor:- water soluble?- lipid soluble?p- pass the BBB?

SO……- Drug structure,- Receptor structure,

Ch i l f i fl i d- Chemical forces influencing drug-receptorinteraction,Drug solubility in water or lipid- Drug solubility in water or lipid,

- Function of receptor in the environment,

ALL THIS will confer the SPECIFICITY ofA drug

Drug ReceptorsA ti h d bi d t• Action occurs when drug binds to receptor and this action may be:

I h l i d l d– Ion channel is opened or closed– Second messenger is activated

• cAMP cGMP Ca++ inositol phosphates etc• cAMP, cGMP, Ca , inositol phosphates, etc.• Initiates a series of chemical reactions

– Normal cellular function is physically p y yinhibitedor stimulated

– Cellular function is “turned on”Drug receptor function as 2 domain:

1.a ligand binding domain2. message propagation or effector domain

Drug-Receptor Interactions•Drug-receptor interactions serve as signals to trigger acascade of events. This cascade or signaling pathway, is ag g p y,collection of many cellular responses which serve to amplifythe signal and produce a final effect.

•Effectors are thus the molecules that translate the drug-receptor interaction into changes in cellular activity.

• • +• • +EFFECTDRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR

INTERACTION COMPLEX SYSTEM

STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE

SIGNALLING PATHWAY

Receptor Signaling PathwaysReceptor Signaling Pathways

Types of ReceptorsMEMBRANE BOUND RECEPTORS• G-Protein-linked receptors

S t i M i i D i i N d iSerotonin, Muscarinic, Dopaminergic, Noradrenergic• Enzyme receptors

Tyrosine kinaseTyrosine kinase• Ligand-gated ion channel receptors

Nicotinic, GABA, glutamate, , g

INTRACELLULAR AND NUCLEAR RECEPTORSH t• Hormone receptors

• Autocoid receptors• Growth factors receptors• Growth factors receptors• Insulin receptors

1. G protein-linked receptorsp pStructure:

•Single polypeptide chain threaded back and forth resulting in 7 transmembrane å helices

•There’s a G protein attached to the cytoplasmic side of the membrane (functions as a

it h)switch).

G-Protein Receptors• Large family of membrane spanning receptors (>100)• Drug binding causes conformational change• Activates G-proteins (G-GDP; G-GTP)• Modulate second messenger systems

– cAMP, ion channels, phospholipases, , p p p– Diffuse, long-acting effects

• Opioids and other neurotransmitters bind to G-protein receptorsp

2. Tyrosine-kinase receptorsStructure:

•Receptors exist as individual polypeptidespolypeptides

•Each has an extracellular signal-binding sitesite

•An intracellular tail with a number of i d i l å h li ityrosines and a single å helix spanning

the membrane

3. Ion channel receptorsp

Structure:

•Protein pores•Protein pores in the plasma membrane

Ion Channel ReceptorsIon Channel Receptors• Drug binding causes conformational changeg g g• Transmembrane pore opens• Ion flux increased• Four families of ion channel receptors identified

Intracellular receptorsN t ll i l t l t d th=Not all signal receptors are located on the

plasma membrane. Some are proteins located in the cytoplasm or nucleus of target cellsthe cytoplasm or nucleus of target cells.=The signal molecule must be able to pass through plasma membranethrough plasma membrane.

Examples:Examples:~Nitric oxide (NO)

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

Steroid (Nuclear) Receptors• Steroids are lipid soluble and traverse cellSteroids are lipid soluble and traverse cell

membrane• Bind to specific cytoplasmic receptors

R t d f ti h• Receptor undergoes conformation change• DNA-binding domain exposed• Initiates or suppressed gene transcriptionInitiates or suppressed gene transcription

Nuclear Receptors

Receptor Signaling Pathways

Second Messengers:Second Messengers:1. Ions (Ca2+, Na+, K+, Cl-)2. cAMP, cGMP, IP3, Diacylglycerol2. cAMP, cGMP, IP3, Diacylglycerol3. DNA binding – Transcriptional regulation.4. Phosphorylated proteins and enzymes p y p y

via tyrosine kinase receptors.

Third Messengers:1. Enzymes (PKC, PKA)

22. Ions (Ca2+, K+)

2 Calcium Ions (Ca2+) and Inositol2. Calcium Ions (Ca ) and InositolTrisphosphate

C l i id l d th AMP•Calcium more widely used than cAMP

•used in neurotransmitters, growth factors, some hormones

•Increases in Ca2+ causes many possible y presponses:

•Muscle cell contractionMuscle cell contraction

•Secretion of certain substance

•Cell division

Two benefits of a signal-transduction gpathway

1 Si l lifi ti1. Signal amplification

2. Signal specificityg p y

Signal amplification•Proteins persist in active form long enough to process numerous molecules of substrate

•Each catalytic step activates more y pproducts then in the proceeding steps

Receptor FamiliesReceptor Families

Summary

= most drugs act through receptors

= in order to be able to bind the receptor----- a change in the conformation of the receptor------ can affect the function

= membrane is important for the drug to enter the cell for drug specificitycell------ for drug specificity

i t d iti tagonists desensitize receptors.antagonists sensitize receptors.