DRUG-INDUCED CONFORMATIONAL...
Transcript of DRUG-INDUCED CONFORMATIONAL...
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DRUG-INDUCEDCONFORMATIONAL CHANGECONFORMATIONAL CHANGE
DR.DATTEN BANGUN MSc,SpFK , p&
DR.TRI WIDYAWATI.MSi
Bagian Farmakologi dan Terapeutik,Fakultas Kedokteran
Universitas Sumatera Utara
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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.
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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.
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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
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Dengan apa berikatan ?
- Protein Molecules
- DNA * antimikroba
* anti neoplasma
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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
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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.
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Receptor ConformationReceptor Conformation
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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
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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
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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
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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
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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
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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
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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
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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
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Receptor Signaling PathwaysReceptor Signaling Pathways
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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
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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).
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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
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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
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3. Ion channel receptorsp
Structure:
•Protein pores•Protein pores in the plasma membrane
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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
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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).
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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
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Nuclear Receptors
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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+)
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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
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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
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Receptor FamiliesReceptor Families
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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.
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