Patrick An Introduction to Medicinal Chemistry 3/e Chapter 5 PROTEINS AS DRUG TARGETS:

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 5Chapter 5

PROTEINS AS DRUG PROTEINS AS DRUG TARGETS:TARGETS:

RECEPTORSRECEPTORS

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ContentsContents1. Structure and function of receptors (2 slides)

1.1. Chemical Messengers (2 slides)1.2. Mechanism (2 slides)

2. The binding site3. Messenger binding

3.1. Introduction3.2. Bonding forces (2 slides)

4. Overall process of receptor/messenger interaction5. Signal transduction

5.1. Control of ion channels (4 slides)5.2. Activation of signal proteins (2 slides)5.3. Activation of enzyme active site

6. Competitive (reversible) antagonists7. Non competitive (irreversible) antagonists8. Non competitive (reversible) allosteric antagonists9. Antagonists by umbrella effect10. Agonists

[24 slides]

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1. Structure and function of receptors1. Structure and function of receptors

• Globular proteins acting as a cell’s ‘letter boxes’Globular proteins acting as a cell’s ‘letter boxes’

• Located mostly in the cell membraneLocated mostly in the cell membrane

• Receive messages from chemical messengers coming from Receive messages from chemical messengers coming from other cellsother cells

• Transmit a message into the cell leading to a cellular effectTransmit a message into the cell leading to a cellular effect

• Different receptors specific for different chemical messengersDifferent receptors specific for different chemical messengers

• Each cell has a range of receptors in the cell membrane Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengersmaking it responsive to different chemical messengers

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Cell

Nerve

Messenger

Signal

Receptor

Nerve

NucleusCell

Response


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Chemical MessengersChemical Messengers

NeurotransmittersNeurotransmitters: Chemicals released from nerve endings which : Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cellsresponsible for messages between individual cells

HormonesHormones: Chemicals released from cells or glands and which : Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells travel some distance to bind with receptors on target cells throughout the bodythroughout the body

• Chemical messengers ‘switch on’ receptors without Chemical messengers ‘switch on’ receptors without undergoing a reaction undergoing a reaction


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Nerve 1

Nerve 2Hormone

Bloodsupply

Neurotransmitters


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Mechanism Mechanism • Receptors contain a binding site (hollow or cleft in the Receptors contain a binding site (hollow or cleft in the

receptor surface) that is recognised by the chemical receptor surface) that is recognised by the chemical messengermessenger

• Binding of the messenger involves intermolecular bondsBinding of the messenger involves intermolecular bonds

• Binding results in an induced fit of the receptor proteinBinding results in an induced fit of the receptor protein

• Change in receptor shape results in a ‘domino’ effectChange in receptor shape results in a ‘domino’ effect

• Domino effect is known as Signal Transduction, leading to a Domino effect is known as Signal Transduction, leading to a chemical signal being received inside the cell chemical signal being received inside the cell

• Chemical messenger does not enter the cell. It departs the Chemical messenger does not enter the cell. It departs the receptor unchanged and is not permanently boundreceptor unchanged and is not permanently bound


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Mechanism Mechanism

CellMembrane

Cell

Receptor

Messenger

message

Induced fit

Cell

Receptor

Messenger

MessageCell

Messenger

Receptor


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ENZYME

2. The binding site2. The binding site

• A hydrophobic hollow or cleft on the receptor surface - A hydrophobic hollow or cleft on the receptor surface - equivalent to the active site of an enzymeequivalent to the active site of an enzyme

• Accepts and binds a chemical messengerAccepts and binds a chemical messenger

• Contains amino acids which bind Contains amino acids which bind the messengerthe messenger

• No reaction or catalysis takes placeNo reaction or catalysis takes place

Binding siteBinding site

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3. Messenger binding3. Messenger binding

• Binding site is nearly the correct shape for the messengerBinding site is nearly the correct shape for the messenger

• Binding alters the shape of the receptor (induced fit)Binding alters the shape of the receptor (induced fit)

• Altered receptor shape leads to further effects - signal Altered receptor shape leads to further effects - signal transductiontransduction

3.1 Introduction3.1 Introduction

MessengerMessenger

Induced fitInduced fit

MM

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• IonicIonic• H-bondingH-bonding• van der Waalsvan der Waals

3.2 Bonding forces3.2 Bonding forces

Example:Example:

Receptor

Binding site

vdwvdwinteractioninteraction

ionicionicbondbond

H-bondH-bond

PheSer

OH

Asp

CO2

3. Messenger binding3. Messenger binding

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3. Substrate binding3. Substrate binding

• Induced fit - Binding site alters shape to maximise Induced fit - Binding site alters shape to maximise intermolecular bondingintermolecular bonding

3.2 Bonding forces3.2 Bonding forces

Intermolecular bonds not optimum length for maximum binding strength

Intermolecular bond lengths optimised

Phe

SerO

H

Asp

CO2 Induced Fit

Phe

SerO

H

Asp

CO2

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4. Overall process of receptor/messenger interaction4. Overall process of receptor/messenger interaction

MM

MM

EERR

• Binding interactions must be:Binding interactions must be: - strong enough to hold the messenger sufficiently long for signal - strong enough to hold the messenger sufficiently long for signal

transduction to take placetransduction to take place - weak enough to allow the messenger to depart - weak enough to allow the messenger to depart • Implies a fine balanceImplies a fine balance• Drug design - designing molecules with stronger binding Drug design - designing molecules with stronger binding

interactions results in drugs that block the binding site - interactions results in drugs that block the binding site - antagonistsantagonists

RR

MM

EERR

Signal transductionSignal transduction

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5. Signal transduction5. Signal transduction5.1 Control of ion channels5.1 Control of ion channels

• Receptor protein is part of an ion channel protein complexReceptor protein is part of an ion channel protein complex

• Receptor binds a messenger leading to an induced fitReceptor binds a messenger leading to an induced fit

• Ion channel is opened or closedIon channel is opened or closed

• Ion channels are specific for specific ions (NaIon channels are specific for specific ions (Na++, Ca, Ca2+2+, Cl, Cl--, K, K++))

• Ions flow across cell membrane down concentration gradientIons flow across cell membrane down concentration gradient

• Polarises or depolarises nerve membranesPolarises or depolarises nerve membranes

• Activates or deactivates enzyme catalysed reactions within Activates or deactivates enzyme catalysed reactions within cellcell

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5. Signal transduction5. Signal transduction

Hydrophilictunnel

Cellmembrane

5.1 Control of ion channels5.1 Control of ion channels

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Cellmembrane

Five glycoprotein subunitstraversing cell membrane

Messenger

Cellmembrane

Receptor

Inducedfit

‘Gating’(ion channel opens)

Cationic ion channels for KCationic ion channels for K++, Na, Na++, Ca, Ca2+2+ (e.g. nicotinic) = excitatory (e.g. nicotinic) = excitatoryAnionic ion channels for ClAnionic ion channels for Cl-- (e.g. GABA (e.g. GABAAA) = inhibitory) = inhibitory

Bindingsite

5.1 Control of ion channels5.1 Control of ion channels


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5.1 Control of ion channels:5.1 Control of ion channels:

Induced fit and opening

of ion channel

IONCHANNEL

(open)

Cell

Cellmembrane

MESSENGER

Ionchannel

Ionchannel

Cellmembrane

IONCHANNEL

(closed)

Cell

RECEPTORBINDING

SITE

Lock Gate Ion

channelIon

channelCell

membraneCell

membrane

MESSENGER


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5.2 Activation of signal proteins5.2 Activation of signal proteins• Receptor binds a messenger leading to an induced fitReceptor binds a messenger leading to an induced fit• Opens a binding site for a signal protein (G-protein)Opens a binding site for a signal protein (G-protein)• G-Protein binds, is destabilised then splitG-Protein binds, is destabilised then split

messenger

G-proteinsplit

inducedfit

closed open


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5.2 Activation of signal proteins5.2 Activation of signal proteins• G-Protein subunit activates membrane bound enzymeG-Protein subunit activates membrane bound enzyme

Binds to allosteric binding siteBinds to allosteric binding siteInduced fit results in opening of active siteInduced fit results in opening of active site

• Intracellular reaction catalysedIntracellular reaction catalysed

active site(closed)

active site(open)

Enzyme

Intracellular reaction

Enzyme


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5.3 Activation of enzyme active site5.3 Activation of enzyme active site• Protein serves dual role - receptor plus enzymeProtein serves dual role - receptor plus enzyme• Receptor binds messenger leading to an induced fitReceptor binds messenger leading to an induced fit• Protein changes shape and opens active siteProtein changes shape and opens active site• Reaction catalysed within cellReaction catalysed within cell

closed

messenger

inducedfit

active site open

intracellular reaction

closed

messenger


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6. Competitive (reversible) antagonists6. Competitive (reversible) antagonists

• Antagonist binds reversibly to the binding site Antagonist binds reversibly to the binding site • Intermolecular bonds involved in bindingIntermolecular bonds involved in binding• Different induced fit means receptor is not activatedDifferent induced fit means receptor is not activated• No reaction takes place on antagonistNo reaction takes place on antagonist• Level of antagonism depends on strength of antagonist Level of antagonism depends on strength of antagonist

binding and concentrationbinding and concentration• Messenger is blocked from the binding site Messenger is blocked from the binding site • Increasing the messenger concentration reverses antagonismIncreasing the messenger concentration reverses antagonism

AnAn

EERR

MM

AnAn

RR

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7. Non competitive (irreversible) antagonists7. Non competitive (irreversible) antagonists

• Antagonist binds irreversibly to the binding siteAntagonist binds irreversibly to the binding site• Different induced fit means that the receptor is not activated Different induced fit means that the receptor is not activated • Covalent bond is formed between the drug and the receptorCovalent bond is formed between the drug and the receptor• Messenger is blocked from the binding site Messenger is blocked from the binding site • Increasing messenger concentration does not reverse Increasing messenger concentration does not reverse

antagonismantagonism

X

OH OH

X

O

Covalent Bond

Irreversible antagonism

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8. Non competitive (reversible) allosteric antagonists8. Non competitive (reversible) allosteric antagonists

• Antagonist binds reversibly to an allosteric site Antagonist binds reversibly to an allosteric site • Intermolecular bonds formed between antagonist and binding Intermolecular bonds formed between antagonist and binding

sitesite• Induced fit alters the shape of the receptorInduced fit alters the shape of the receptor• Binding site is distorted and is not recognised by the messengerBinding site is distorted and is not recognised by the messenger• Increasing messenger concentration does not reverse Increasing messenger concentration does not reverse

antagonismantagonism

ACTIVE SITE (open)

ENZYMEReceptor

AllostericAllostericsitesite

Binding siteBinding site

(open)ENZYMEReceptor

Inducedfit

Binding siteBinding siteunrecognisableunrecognisable

Antagonist

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9. Antagonists by umbrella effect9. Antagonists by umbrella effect• Antagonist binds reversibly to a neighbouring binding site Antagonist binds reversibly to a neighbouring binding site • Intermolecular bonds formed between antagonist and Intermolecular bonds formed between antagonist and

binding sitebinding site• Antagonist overlaps with the messenger binding siteAntagonist overlaps with the messenger binding site• Messenger is blocked from the binding siteMessenger is blocked from the binding site

Antagonist

Binding sitefor antagonist

Binding sitefor messenger

messenger

Receptor Receptor

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10. Agonists10. Agonists• Agonist binds reversibly to the binding site Agonist binds reversibly to the binding site • Similar intermolecular bonds formed as to natural messengerSimilar intermolecular bonds formed as to natural messenger• Induced fit alters the shape of the receptor in the same way as Induced fit alters the shape of the receptor in the same way as

the normal messengerthe normal messenger• Receptor is activatedReceptor is activated• Agonists are often similar in structure to the natural Agonists are often similar in structure to the natural

messengermessenger

EE

AgonistAgonist

RR EE

AgonistAgonist

RR

Signal transductionSignal transduction

AgonistAgonist

RR

Induced fitInduced fit

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 5 PROTEINS AS DRUG TARGETS:

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