Chemistry of Statins as Anti-cholesterol agents Flashcards
What is the function of cholesterol?
What transports cholesterol round the body/blood supply?
How does excess cholesterol lead to CVS disease?
Important in biosynthesis + cell membrane structure
Hydrophobic molecule
Transported round the body by LDLs + HDLS
- LDLs = carry cholesterol to cells
- HDLs = carry cholesterol from cells to liver
Excess cholesterol in the blood can cause fatty plaques in arteries leading to a risk of atherosclerosis, clot formation, stroke + heart attack
Mortality associated with high levels of LDLs or low levels of HDLs
What do statins target?
HMG - CoA reductase
Inhibit enzyme which prevents synthesis of cholesterol
Target the enzyme catalysing rate limiting step in the biosynthetic pathway
Describe the catalytic mechanism of HMG- CoA
Involves 2 hydride transfers
2 molecules of cofactor required (NADPH) (CoA)
Lys, His, Glu + Asp are involved in reaction]Histidine acts as acid catalyst
Lystine stabilises -ively charged oxygen of mevaldyl-CoA + transition state
Lowers activation energy of first step
Glutamine acid acts as acid catalyst
Aspartate stabilises Gu-559 + Lys-691
Describe how Compactin was identified
Identified by screening natural products produced by microorganisms
Microbes lacking HMGR might produce HMGR inhibitors to inhibit microbes
Isolated from Pencillum
10,000 higher affinity
Never reached market
Examples of type 1 statins
Describe chemical structure
What are the disadvantages of type 1?
e.g. lovastatin, simvastatin, pravastatin
Lovastatin isolated from Aspergillus Terreus
Revolutionised treatment of hypercholesterolaemia
Disadvantages include various side effects, difficult to synthesise, large no. of assymetric centres
Examples of Type 2 Statins
Which statin is the most potent?
Which statin is the least hydrophobic?
Which statin is the most hydrophobic?
What are the effects of a statin with a lower hydrophobic character?
What do hydrophobic statins target? + why?
Where does cholesterol synthesis takes place?
Why are there side effects? + what is the common side effect?
e.g. fluvastatin, atrovastatin, cerivastatin, rosuvastatin,
Synthetic agents
Contain larger hydrophobic moiety with no assymetric centres
Easier to synthesise
Structures share similar featurs
Rosuvastatin is the most potent (sulfonamide group)
Cerivastatin is most hydrophobic
Pravastatin + Rosuvastatin are least hydrophobic
Statins with lower hydrophobic character target liver cells + lower side effects, do not cross cell membranes easily
Liver cells have transport proteins that other cells do not have
Cholesterol synthesis mostly takes place in liver cells
Side effects due to inhibition of HMGR in other cells
Common side effects Myalgia
Rhabdomyolysis = severe muscle toxicity
Cerivastatin was withdrawn due to rhabdomyolysis
Describe mode of action of Statins
Competitive inhibitors of HMGR
Hydrophobic moiety forms additional binding interactions
Binds more strongly than natural substrate
Same binding interactions for polar head
Statins mimic mevaldyl CoA
Describe the binding interactions of statins
Which functional group interacts with Arg-568?
Which functional group interacts with Ser-565?
What functional groups in both type 1 + 2 statins bind at the same region?
What functional group interacts with Arg-590?
In Rosuvastatin, what does the sulfone group interact with?
Polar head binds to substrate
Hydrophobic moiety doesn’t bind to pocket SCoA
Enzyme is flexible + alters shape to accomodate statins
Hydrophobic pocket is created to bind hydrophobic moiety
Methylethyl substituent of type 2 statins bind to the same region as decalin ring of type 1
Arg-590 forms polar interactions with fluorophenyl substituent
Amide group forms additional hydrogen bonding with Ser-565
- Rosuvastatin forms additional h-bonding interactions*
- Sulfone oxygen froms hydrogen bonding interaction with Ser-565*
- Sulfone group interacts uniquely with Arg-568*
- Sulfone group important for binding + selectivity*
