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Semester 1
Inflammatory diseases
Leoni NSAID medchem
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Cam Berry
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Cards (62)
What are the learning outcomes for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in PHA-6020Y?
Recap of the
COX
pathway
Know that NSAIDs inhibit all three branches of the COX pathway
Describe the relationship between
aspirin
receptor site and the COX active site
Understand aspirin’s mechanism of action
Awareness of alternatives to aspirin as antiplatelet drugs that inhibit COX active site
Apply medicinal chemistry knowledge to design selective COX inhibitors
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Which three branches of the COX pathway are affected by NSAIDs?
Thromboxane
,
prostacyclin
, and the
prostaglandins
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What is the relationship between the aspirin receptor site and the COX active site?
Aspirin binds irreversibly to the aspirin receptor site, blocking
arachidonic acid
access to the COX active site
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What is aspirin’s mechanism of action?
Aspirin irreversibly blocks the
COX
active site by binding to a
serine residue
, preventing
arachidonic acid
from accessing the enzyme
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What are the alternatives to aspirin as antiplatelet drugs that competitively inhibit the COX active site?
Other salicylates
Ibuprofen
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How can medicinal chemistry knowledge be applied for the design of inhibitors suitable to selectively fit the COX family of proteins?
By tailoring chemical interactions and steric requirements to fit specific COX isoforms
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What is the COX pathway also known as?
Prostaglandin synthase pathway
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What molecule fits into the active site of the cyclooxygenase enzyme Cox to access the prostaglandin?
Arachidonic acid
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What is the first prostaglandin produced in the COX pathway?
Prostaglandin G2
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What is prostaglandin G2 converted to in the COX pathway?
Prostaglandin H2
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Which prostaglandin is produced by the conversion of prostaglandin H2?
Prostaglandin D2
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What is prostaglandin E2 also known as?
PGE2
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What is prostaglandin F2α also known as?
PGF2α
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What enzyme converts prostaglandin H2 to thromboxane A2?
Thromboxane synthase
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What is the product of thromboxane synthase in the COX pathway?
Thromboxane A2
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What are the effects of prostaglandins on the body?
Prostaglandins cause
inflammatory
responses
, swelling, inflammation, pain, and fever
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What is the function of platelet aggregation inducers?
Platelet aggregation inducers stimulate the clumping together of
platelets
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What is the function of platelet aggregation inhibitors?
Platelet aggregation inhibitors prevent
platelets
from clumping together
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Where are phospholipids primarily located in cells?
In the cell membrane
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What is produced from the degradation of cell membrane phospholipids?
Arachidonic acid
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What enzyme does arachidonic acid bind to in the COX pathway?
Cyclooxygenase
enzyme
Cox
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What are the physiological effects of prostaglandins?
Inflammatory
Cause swelling
Cause inflammation
Cause pain
Cause fever
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At
what physiological pH is aspirin deprotonated?
At physiological pH
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What reference is given for COX inhibition?
N Engl J Med
,
2001
, 345,
1809
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How does the hydroxyl group on serine residues facilitate aspirin's transesterification?
The hydroxyl group facilitates the transesterification of aspirin's
acyl group
It attacks the
electrophilic carbonyl carbon
of aspirin
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How does the carboxylate anion of aspirin facilitate its transesterification with serine residues?
Removes proton on serine
Makes oxygen more nucleophilic
Increases serine's ability to attack the
carbonyl
group
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Which amino acid residue forms a hydrogen bond with the carbonyl group on aspirin?
Tyrosine
residue
385
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Why is aspirin’s inhibition of COX considered irreversible?
A covalent bond is formed between aspirin and
serine
residues
It cannot be easily reversed without the synthesis of new COX enzymes
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What type of protein is COX?
COX is a
homo dimer
protein containing two identical
polypeptide
chains
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What feature allows arachidonic acid to enter the COX active site?
A
hydrophobic
channel leading to the active site
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What moiety constitutes the active site of COX enzymes?
A
heme
moiety
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How does aspirin inhibit COX without competing for the active site?
Aspirin irreversibly binds to a
serine
residue, preventing
arachidonic acid
from reaching the
heme active site
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To which serine residue is the acyl group of aspirin transferred?
Serine 529
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How does acylated serine 529 affect access to the COX active sites?
It blocks the access to the
enzyme
active sites, preventing arachidonic acid from binding to the
heme moiety
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How do non-selective NSAIDs like ibuprofen inhibit COX?
They act as competitive inhibitors of both
COX-1
and
COX-2
enzymes
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What is the chemical name for aspirin?
Acetylsalicylic acid
(
ASA
)
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Is aspirin selective for COX-1 or COX-2 enzymes?
No, it is non-selective for COX-1 and COX-2 enzymes
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To which residue do non-selective NSAIDs bind?
Arg120
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What type of interaction do non-selective NSAIDs form with Arg120?
Ionic interaction
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Are non-selective NSAIDs competitive or irreversible inhibitors of COX-1 and COX-2?
Competitive inhibitors of
both
COX-1
and
COX-2
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