1 Platelets produce thromboxanes (stimulate vasoconstriction, clott od vessels produce prostacyclins late vasodilation, inhibit clotting) Reduce inflammatory response, transm pain, regulate allergy and immunit Leukotrienes lead to inflammatio (asthma, heart attack, anaphylaxi
14
Embed
Platelets produce thromboxanes (stimulate vasoconstriction, clotting)
Leukotrienes lead to inflammation (asthma, heart attack, anaphylaxis). Reduce inflammatory response, transmit pain, regulate allergy and immunity. Platelets produce thromboxanes (stimulate vasoconstriction, clotting). Blood vessels produce prostacyclins - PowerPoint PPT Presentation
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1
Platelets produce thromboxanes(stimulate vasoconstriction, clotting)
Blood vessels produce prostacyclins(stimulate vasodilation, inhibit clotting)
Reduce inflammatory response, transmit pain, regulate allergy and immunity
Leukotrienes lead to inflammation (asthma, heart attack, anaphylaxis)
• Stored as C2-ester of phospholipids (released by phospholipase A2)
• Hormone-like molecules, decompose within seconds or minutes (have very local effects)
• Pain, fever, coagulation, blood pressure, and reproduction
3
Prostaglandins
• Prostaglandin H2 synthase forms a cyclopentane ring in linear arachidonic acid
• Enzyme has 2 catalytic activities:– Cyclooxygenase (adds two O2)– Peroxidase (converts OOH group to OH)
• Commonly called COX• Aspirin is an irreversible inhibitor of COX
(inactivates enzyme by acetylating active site Ser and blocking active site from reacting with substrate– Analgesic, antipyretic, anti-inflammatory
Ser-ÖH
4
COX
• NSAIDs (NonSteroidal Anti-Inflammatory Drugs)
• Acetaminophen and ibuprofen are noncovalent inhibitors of COX
• COX-1 and COX-2 isoforms (60% identical)• COX-2 inhibitors lack side effects of other NSAIDS
– COX-1 expressed ubiquitously, maintains homeostasis – COX-2 expressed in certain tissues during inflammation
response and is responsible for elevated prostaglandin levels
• Aspirin and ibuprofen are nonspecific NSAIDs, have side effects (gastrointestinal ulceration)
5
COX-2•Structure-based drug design of selective COX-2 inhibitors•COX-2 active site ~20% larger than COX-1 (make a bigger inhibitor that cannot fit into COX-1 site)
•Rofecoxib (Vioxx) popular and effective, but withdrawn due to unanticipated cardiac side effects (mechanism may involve inhibition of prostacyclin synthesis (leaving thromboxane synthesis less affected)
•Acetaminophen effective, but low affinity for COX-1,2 (binds COX-3, which is expressed in the central nervous system)
COXinhibitor
6
Drug Design
• Drug Discovery: How?Screening large numbers of compounds for inhibition
of enzymatic activity or receptor signaling
Measure KI(or KI’)
Good lead compound has KI < 1MWhy is high affinity necessary?-specificity!!!!!-dose!!!!!!!Design related compounds using combinatorial
chemical techniques
7
Structure-based design
• X-ray, NMR• What does the active site
look like empty and with the substrate in it?
• Look at structural and electrostatic properties of active site and try to better fit/fill it.
For a candidate…• Quantum mechanical calculation of charge
distribution• Docking simulations• Determine structure of complex, revise inhibitor
structure and re-assay KI
8
Bioavailability & ToxicityTo cause desired response:
– Drug must arrive at high enough concentration– Drug must arrive to the location of the target protein
Oral drugs (cheapest)– Acid-stable (stomach)– Membrane-permeable (gut-blood transfer, so can’t be highly charged))– Don’t bind tightly to other things (lipophilic drugs sequestered in
membrane/adipocytes)– Survive detoxifying enzymes in the liver (portal vein drains intestine
directly to liver)– Avoid rapid excretion by kidneys– Must pass from capillaries to tissues– (for brain) must pass blood-brain barrier, which blocks polar substances– (for intracellular protein) must pass plasma (and other) membrane(s)