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Enzymes and Receptors as Drug Targets - Coggle Diagram
Enzymes and Receptors as Drug Targets
Enzymes
Structure and Function:
Globular proteins (3rd degree and 4th degree structures)
-Catalysts (speed up reactions)
Lower activation energy
The active site:
Hydrophobic hollow or cleft on the enzyme surface
Accepts reactants (substrates and cofactors)
Contains amino acids which
bind reactants (substrates and cofactor)
Participate in the enzyme-catalysed reactions
Are specific for what they will catalyse
Are reusable
Methods of enzyme catalysis:
Provides a reaction surface (the active site)
Provides a suitable environment (hydrophobic)
Bring reactants together
Position reactants correctly for reaction
Weakens bonds in the reactants
Provide acid/ base catalysis
Provides nucleophilic groups
Stabilises the transition state with intermolecular bonds.
Structure and function of enzymes:
Enzymes lowers the activation energy of reactions
How do enzymes reduce activation energy
Enzyme + substrates form an enzyme-substrate complex
Binding interactions with 'aa' residues hold the substrate in place
Catalytic 'aa' residues (R groups) facilitate the reaction
making or breaking bonds in the substrate
Product is formed and released
Substrate Binding: Bonding forces
Ionic
H-bonding
Van der Waals
Substrate Binding: Induced Fit
Active site is flexible (not precisely complementary to substrate)
Substrate enters active site, active site conformation changes
Amino acids in active site move closer to form chemical bonds with substrate
Strains bonds in substrate
Lowers activation energy of reactions
Intermolecular bonds not optimum length for maximum bonding but when induced fit occurs, the intermolecular bonds lengths optimised and susceptible bonds in substrate strained.
Catalysis mechanism: Acid/ base catalysis
Non-ionised (acts as a basic catalyst where proton 'sink')
Ionised ( acts as an acid catalyst where protons are the source.
Enzyme Inhibition
Overall process of enzyme catalysis
Binding interactions must be strong enough to hold the substrate sufficiently long for the reaction to occur
Interactions must be weak enough to allow the product to depart
Interactions stabilise the transition state
Designing molecules with stronger binding interactions results in enzyme inhibitors which block the active site.
Reversible Inhibitor:
Inhibitor binds reversibly to the active site
Intermolecular bonds are involved in binding
The inhibitor undergoes no reaction
Inhibition depends on the strength of inhibitor binding and inhibitor concentration
Substrate is blocked from the active site
Increasing substrate concentration reverses inhibition
Inhibitor likely to be similar in structure to substrate, product or cofactors
Irreversible Inhibitors:
Inhibitor binds irreversibly to the active site
Covalent bond formed between the drug and the enzyme
Substrate is blocked from the active site
Increasing substrate concentration does not reverse inhibition
Inhibitor likely to be similar in structure to the substrate.
Examples of reversible inhibitors
Antidepressants
ACE inhibitors
Diuretics
Kinase Inhibitors
Protease Inhibitors
Statins
Sulfonamides
Irreversible Inhibitors
Cephalosporins
Nerve gases
Penicillin
Proton pump inhibitors
Orlistat
Irreversible Inhibitors- Orlistat
Orlistat is an anti-obesity drug that inhibits pancreatic lipase
The enzyme is blocked from digesting fats in the intestine
Fatty acids and glycerol are less absorbed as a result
Leads to reduced biosynthesis of fat in the body
Orlistat interacts with a serine group in the enzyme
The orlistat ketone breaks as the 'O' on the serine binds to the carbon
The 'H+' floats away
The ring breaks to stabilise the new C-O covalent bond
H+ is reattached
Allosteric Inhibitors:
Inhibitor binds reversibly to the allosteric site
Intermolecular bonds are formed
Induced fit alters the shape of the enzyme
Since active site is distorted it is not recognised by the substrate
Increasing substrate concentration does not reverse inhibition
Allosteric inhibitors do not have to be similar in structure to the substrate
Transition-state Inhibitors
Drugs designed to mimic the transition state of an enzyme-catalysed reaction
Transition-state inhibitors are likely to bind more strongly than drugs mimicking the substrate or product.
Transition states are high energy, transient species and cannot be isolated or synthesised.
Design is based on reaction intermediates so are closer in character to transition states than substrates or products
These drugs mimic the stereochemistry and binding properties of the reaction intermediate but is stable.
Suicide Substrates:
Agents which are converted to irreversible inhibitors by the enzyme-catalysed reaction
React with the target enzyme once formed
Enzyme targets for useful medications
Antibacterial agents
Dihydropteroate synthetase, transpeptidase
Antiviral agents
HIV reverse transcriptase, HIV protease, viral DNA polymerase
Anti-inflammatory agents
Cyclooxygenase
Cholesterol lowering agents
HMG-CoA reductase
Antidepressants
Monoamine oxidase
Anticancer agents
Tyrosine kinase, dihydrofolate reductase, thymidylate synthase, aromatase etc
Antihypertensive agent
Renin, angiotensin converting enzyme
Treatment of male erectile dysfunction
Phosphodiesterase
Anti-gout agents
Xanthine oxidase
Anti-ulcer agents
Proton pump
Alzheimers disease
Cholinesterase
Diuretics
Carbonic anhydrase
Design of Agonists
Agonists vs Antagonists:
Agonists are drugs designed to mimic the natural messenger
Antagonists are drugs designed to block the natural messenger
Design of Agonists:
Agonists bind reversibly to the binding site and produce the same induced fit as the natural messenger- receptor is activated
Similar intermolecular bonds formed as with natural messenger
Agonists are often similar in structure to the natural messenger.
Requirements:
The agonist must have correct binding groups
The binding groups must be correctly positioned to interact with complementary binding regions ( regions in binding site)
The drug must have the correct shape to fit the binding site.
Size and Shape:
Agonist must have correct size and shape to fit binding site
Groups preventing access are called steric shields to steric blocks
Natural messenger binding:
Receptors contain a binding site, which is nearly the correct shape for messenger
Binding alters the shape of the receptor (induced fit)
Altered receptor shape leads to further effects- signal transduction
Chemical messenger does not enter the cell, is not permanently bound and departs unchanged.
Design of Antagonist
Antagonists are drugs designed to block the natural messenger
Antagonists tend to have stronger and/ or more binding interactions, resulting in a different induced-fit such that the receptor is not activated.
Reversible Antagonists:
Antagonist binds reversibly to the binding site
Intermolecular bonds involved in binding
Different induced fit means receptor is not activated
The antagonist does not undergo any reaction
Level of antagonism depends on strength of antagonist binding and concentration
Messenger is blocked from the binding site
Increasing the messenger concentration reverses antagonism
Antagonists bind to the binding site but fail to produce the correct induced fit - receptor is not activated
Normal messenger is blocked from binding
Antagonists can form binding interactions with binding regions in the binding site not used by the natural messenger
Irreversible Antagonists:
Antagonist binds irreversibly to the binding site
Different induced fit means that the receptors is not activated.
Covalent bond is formed between the drug and the receptors
Messenger is blocked from the binding site
Increasing messenger concentration does not reverse antagonism
Often used to label receptors
Allosteric Antagonists
Antagonist binds reversibly to an allosteric binding site
Intermolecular bonds formed between antagonist and binding site
Induced fit alters the shape of the receptor
Binding site is distorted and is not recognised by the messenger
Increasing messenger concentration does not reverse antagonism
Antagonists by the Umbrella Effect:
Antagonist binds reversibly to a neighbouring binding site
Intermolecular bonds formed between antagonist and binding site
Antagonist overlaps the messenger binding site
Messenger is blocked from the binding site
Partial Agonists:
Agents who act as agonists but produce a weaker effect
Agent binds but does not produce the ideal induced-fit for maximum effect
Agents bind to binding site in two different modes, one where the agent acts as an agonist and one where it acts as an antagonist
Agent binds as an agonist to one receptor subtype, but as an antagonist to another receptor subtype.
Inverse Agonist:
Properties shared with antagonists:
Bind to receptor binding sites with different induced-fit from the normal messenger
The receptor is not activated
Normal messenger is blocked from binding to the binding site
Properties not shared with antagonists:
Block any inherent activity related to the receptor (e.g GABA receptor )
Inherent activity= level of activity present in the absence of a chemical messenger
Receptors are in an equilibrium between constitutionally active and inactive forms