1 © Patrick Patrick An Introduction to Medicinal Chemistry An Introduction to Medicinal Chemistry 3/e 3/e Chapter 4 Chapter 4 PROTEINS AS DRUG PROTEINS AS DRUG TARGETS: TARGETS: ENZYMES ENZYMES
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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal
ChemistryChemistry 3/e 3/e
Chapter 4Chapter 4
PROTEINS AS DRUG PROTEINS AS DRUG TARGETS:TARGETS:ENZYMESENZYMES
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ContentsContents
1. Structure and function of enzymes (3 slides)2. The active site3. Substrate binding
3.1. Induced fit3.2. Bonding forces (5 slides)
4. Catalysis mechanisms4.1. Acid/base catalysis4.2. Nucleophilic residues
5. Overall process of enzyme catalysis6. Competitive (reversible) inhibitors7. Non competitive (irreversible) inhibitors8. Non competitive (reversible) allosteric inhibitors (2 slides)
[18 slides]
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1. Structure and function of enzymes1. Structure and function of enzymes
• Globular proteins acting as the body’s catalystsGlobular proteins acting as the body’s catalysts• Speed up time for reaction to reach equilibriumSpeed up time for reaction to reach equilibrium• Lower the activation energy of a reactionLower the activation energy of a reaction
Example:Example:
LDH = Lactate dehydrogenase (enzyme)NADH = Nicotinamide adenosine dinucleotide (reducing agent & cofactor)Pyruvic acid = Substrate
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Lowering the activation energy of reactionLowering the activation energy of reaction
Act. energy
Transition state
WITHOUT ENZYME
Product
Startingmaterial
Energy
WITH ENZYME
Product
Startingmaterial
Energy
∆G
Newtransition
state
∆G
Act. energy
• Enzymes lower the activation energy of a Enzymes lower the activation energy of a reaction but reaction but G remains the sameG remains the same
1. Structure and function of enzymes1. Structure and function of enzymes
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Methods of enzyme catalysisMethods of enzyme catalysis
• Provide a reaction surface (the active site)Provide a reaction surface (the active site)
• Provide a suitable environment (hydrophobic)Provide a suitable environment (hydrophobic)
• Bring reactants togetherBring reactants together
• Position reactants correctly for reactionPosition reactants correctly for reaction
• Weaken bonds in the reactantsWeaken bonds in the reactants
• Provide acid / base catalysisProvide acid / base catalysis
• Provide nucleophilesProvide nucleophiles
1. Structure and function of enzymes1. Structure and function of enzymes
LinkLinkLink
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2. The active site2. The active site
• Hydrophobic hollow or cleft on the enzyme surfaceHydrophobic hollow or cleft on the enzyme surface
• Accepts reactants (substrates and cofactors)Accepts reactants (substrates and cofactors)
• Contains amino acids whichContains amino acids which - bind reactants (substrates and cofactors)- bind reactants (substrates and cofactors) - catalyse the reaction- catalyse the reaction
ENZYME
Active siteActive site
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Substrate Binding
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3. Substrate binding3. Substrate binding
• Active site is nearly the correct shape for Active site is nearly the correct shape for the substratethe substrate
• Binding alters the shape of the enzyme Binding alters the shape of the enzyme (induced fit)(induced fit)
• Binding will strain bonds in the substrateBinding will strain bonds in the substrate• Binding involves intermolecular bonds Binding involves intermolecular bonds
between functional groups in the substrate between functional groups in the substrate and functional groups in the active siteand functional groups in the active site
3.1 Induced fit3.1 Induced fit
Induced fitInduced fit
SubstrateSubstrateSS
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Forces Involved in Binding
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• IonicIonic• H-bondingH-bonding• van der Waalsvan der Waals
3.2 Bonding forces3.2 Bonding forces
Example:Example:
SS
Enzyme
Active site
vdwvdwinteractioninteraction
ionicionicbondbond
H-bondH-bond
PheSer
OH
Asp
CO2
3. Substrate binding3. Substrate binding
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Ionic
H3CC
C
O
O
O
• IonicIonic• H-bondingH-bonding• van der Waalsvan der Waals
3.2 Bonding forces3.2 Bonding forces
Example:Example: Binding of pyruvic acid in LDH Binding of pyruvic acid in LDH
OH
H3N
H-Bond
Ionicbond
Possible interactions vdw-interactions
H3CC
C
O
O
O
3. Substrate binding3. Substrate binding
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• Induced fit - Active site alters shape to Induced fit - Active site alters shape to maximise intermolecular bondingmaximise intermolecular bonding
3.2 Bonding forces3.2 Bonding forces
Intermolecular bonds not optimum length for maximum bonding
Intermolecular bond lengths optimisedSusceptible bonds in substrate strainedSusceptible bonds in substrate more easily broken
SS Phe
SerOH
Asp
CO2 Induced fit
SSPhe
SerOH
Asp
CO2
3. Substrate binding3. Substrate binding
Link
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Example:Example: Binding of pyruvic acid in LDH Binding of pyruvic acid in LDH
O
H
H3N
H3CC
C
O
O
O
O
O
O
3. Substrate binding3. Substrate binding
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Example:Example: Binding of pyruvic acid in LDH Binding of pyruvic acid in LDH
O
H
H3N
pi bondpi bondweakenedweakened
H3CC
C
O
O
O
3. Substrate binding3. Substrate binding
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4. Catalysis mechanisms4. Catalysis mechanisms
• HistidineHistidine
4.1 Acid/base catalysis4.1 Acid/base catalysis
4.2 Nucleophilic residues4.2 Nucleophilic residues
NNH
+H
-H NNH
H
Non-ionisedNon-ionisedActs as a basic catalystActs as a basic catalyst(proton 'sink')(proton 'sink')
IonisedIonisedActs as an acid catalystActs as an acid catalyst(proton source)(proton source)
H3N CO2
OH
H
L-SerineL-Serine
H3N CO2
SH
H
L-CysteineL-Cysteine
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Catalytic Mechanisms: Serine Acting as a Nucleophile
LinkLink
Serine side chain
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5. Overall process of enzyme catalysis5. Overall process of enzyme catalysis
SS
EE
ES
PP
EE
EP
PP
EE
E + P
EE
SS
E + S
EE
• Binding interactions must be;Binding interactions must be; - strong enough to hold the substrate - strong enough to hold the substrate
sufficiently long for the reaction to sufficiently long for the reaction to occuroccur
- weak enough to allow the product to - weak enough to allow the product to depart depart
• Implies a fine balanceImplies a fine balance• Drug design - designing molecules with Drug design - designing molecules with
stronger binding interactions results in stronger binding interactions results in enzyme inhibitors which block the active siteenzyme inhibitors which block the active site
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Competitive Inhibitors
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6. Competitive (reversible) inhibitors6. Competitive (reversible) inhibitors
• Inhibitor binds reversibly to the active site Inhibitor binds reversibly to the active site • Intermolecular bonds are involved in bindingIntermolecular bonds are involved in binding• No reaction takes place on the inhibitorNo reaction takes place on the inhibitor• Inhibition depends on the strength of Inhibition depends on the strength of
inhibitor binding and inhibitor concentrationinhibitor binding and inhibitor concentration• Substrate is blocked from the active site Substrate is blocked from the active site • Increasing substrate concentration reverses Increasing substrate concentration reverses
inhibitioninhibition• Inhibitor likely to be similar in structure Inhibitor likely to be similar in structure
to the substrateto the substrate
II
EEEE
SS
II
EE
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Irreversible
Inhibitors
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7. Non competitive (irreversible) inhibitors7. Non competitive (irreversible) inhibitors
• Inhibitor binds irreversibly to the active site Inhibitor binds irreversibly to the active site • Covalent bond formed between the drug and the enzymeCovalent bond formed between the drug and the enzyme• Substrate is blocked from the active site Substrate is blocked from the active site • Increasing substrate concentration does not reverse inhibitionIncreasing substrate concentration does not reverse inhibition• Inhibitor likely to be similar in structure to the substrateInhibitor likely to be similar in structure to the substrate
X
OH OH
X
O
Covalent Bond
Irreversible inhibition
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ACTIVE SITE (open)
ENZYMEEnzyme
8. Non competitive (reversible) allosteric inhibitors8. Non competitive (reversible) allosteric inhibitors
• Inhibitor binds reversibly to the allosteric site Inhibitor binds reversibly to the allosteric site • Intermolecular bonds are formedIntermolecular bonds are formed• Induced fit alters the shape of the enzymeInduced fit alters the shape of the enzyme• Active site is distorted and is not recognised by the substrateActive site is distorted and is not recognised by the substrate• Increasing substrate concentration does not reverse inhibitionIncreasing substrate concentration does not reverse inhibition• Inhibitor is not similar in structure to the substrateInhibitor is not similar in structure to the substrate
AllostericAllostericsitesite
Active siteActive site
(open)ENZYMEEnzyme
Inducedfit
Active siteActive siteunrecognisableunrecognisable
Allostericinhibitor
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8. Non competitive (reversible) allosteric inhibitors8. Non competitive (reversible) allosteric inhibitors
• Enzymes with allosteric sites often at start Enzymes with allosteric sites often at start of biosynthetic pathwaysof biosynthetic pathways
• Enzyme is controlled by the final product of Enzyme is controlled by the final product of the pathwaythe pathway
• Final product binds to the allosteric site Final product binds to the allosteric site and switches off enzymeand switches off enzyme
• Inhibitor may have a similar structure to Inhibitor may have a similar structure to the final productthe final product
P’’’P’’P’
Biosynthetic pathway
Feedback controlInhibition
PPSS
(open)ENZYMEEnzyme
Link
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