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Pharmacodynamics > Drug Targets: Enzymes > Flashcards

Drug Targets: Enzymes Flashcards

1
Q

Define enzyme

A

Substance that acts as a catalyst in living organisms, regulating the rate at which chemical reactions proceed without itself being altered in the process

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2
Q

Binding interactions for enzyme catalysis should be?

A

Strong enough to hold substrate long enough for reaction to occur
Weak enough to allow product to leave

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3
Q

Michaelis-menten equation relates reaction rate to?

A

Substrate concentration

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4
Q

What is vmax?

A

Enzyme maximum reaction rate

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5
Q

Km ( Michaelis constant) is

A

Measure of affinity of the substrate for the enzyme

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6
Q

How to measure km?

A

Half of Vmax

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7
Q

Lineweaver burk plot, function?

A

Turn michaelis-menten equation into a straight line plot

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8
Q

Benefit of lineweaver burk plot

A

Allows you to estimate vmax and km more accurately

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9
Q

3 types of reversible inhibition

A

Competitive
Non-competitive
Uncompetitive

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10
Q

Inhibitor competes with substrate for active site

A

Competitive inhibitor

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11
Q

How to overcome competitive inhibition?

A

Increase levels of substrate

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12
Q

Inhibitor binds to a different site (allosteric site)

A

Non-competitive

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13
Q

Can you overcome non-competivite inhibition by increasing substrate levels? And why?

A

No because it is binding to a different site

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14
Q

Inhibitor binds to a separate and distinct site

A

Uncompetitive inhibitor

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15
Q

Condition of uncompetitive inhibition

A

Can only bind to the site if the substrate is present

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16
Q

Irreversible inhibitors result in permanent inactivation of enzyme, why?

A

Because they form covalent bonds

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17
Q

In the Lineweaver-burk plot explain what happens to km and Vmax for competitive inhibition

A

Km is increased
Vmax is unaffected

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18
Q

In the Lineweaver-burk plot explain what happens to km and Vmax for non-competitive inhibition

A

Km is unaffected because inhibitor is not interfering with affinity of active site (it’s binding to a different site)
Vmax is reduced

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19
Q

In the Lineweaver-burk plot explain what happens to km and Vmax for uncompetitive inhibition

A

Km is reduced
Vmax is reduced

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20
Q

Covalent irreversible drugs

A

Bind specifically to drug target and form a precisely directed, permanent bond with their target

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21
Q

Example of therapeutic important enzyme inhibitors

A

Aspirin, penicillin, ace inhibitors, sildenafil, oseltamivir

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22
Q

ACE

A

Angiotensin converting enzyme

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23
Q

What does ACE do?

A

Key enzyme in converting angiotensin 1 to angiotensin 2 ( vasoactive hormone)

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24
Q

Ace inhibitor does what?

A

Inhibits ace from converting angiotensin 1 to2

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25
Q

What type of inhibitor is an ACE inhibitor?

A

Competitive inhibitor

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26
Q

Angiotensin 2 has effects that can do what to blood pressure?

A

Increase ( vasoconstriction)

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27
Q

Sildenafil also known as

A

Viagra

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28
Q

Sildenafil is what type of inhibitor?

A

Competitive inhibitor

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29
Q

What does sildenafil inhibit?

A

Phosphodiesterase V

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30
Q

What was sildenafil originally developed for?

A

Treatment for hypertension and angina

31
Q

What was discovered about sildenafil at clinical trials?

A

Found to be effective at inducing erections than treating angina

32
Q

How does sildenafil allow for more vasodilation?

A

Nitric oxide binds to receptors in smooth muscle cells which results in increased levels of cGMP
cGMP is broken down by phosphodiesterase V therefore using inhibitor increases levels of cGMP = more vasodilation

33
Q

Oseltamivir also known as

A

Tamiflu

34
Q

Oseltamivir is what type of inhibitor?

A

Competitive inhibitor

35
Q

Oseltamivir inhibits what?

A

Viral neuraminidase

36
Q

Function a viral neuraminidase

A

Prevents viral replication and release

37
Q

Oseltamivir became a blockbuster how?

A

Through stockpiling for ‘swine flu’ pandemic of 2009

38
Q

What is penicillin?

A

Group of drugs

39
Q

What does penicillin inhibit?

A

Synthesis of bacterial peptidoglycan cell wall

40
Q

Inhibition of cell wall synthesis by penicillin triggers what?

A

Action of autolytic enzymes by destabiling their cell wall located inhibitors

41
Q

Key component of penicillin is?

A

Beta-lactam ring

42
Q

Function of beta-lactams

A

Prevent cross-linking peptides from binding to the retrapeptide side chain so bacteria can’t form an efficient cell wall

43
Q

Bacterial resistance can be achieved from penicillin how?

A

Action of beta-lactamases
(Ironically)

44
Q

Aspirin can be used as both?

A

An anti-inflammatory (NSAID) and antiplatelet drug (blood thinner)

45
Q

Therapeutic action happens by aspirin through which inhibition? And of what?

A

Irreversible inhibitor of enzyme cycloxygenase (COX)

46
Q

Cox has 2 active sites

A
  • Allows arachidonate acid to be converted to prostaglandin G2
  • produce other prostaglandins
47
Q

How does aspirin work as an anti-inflammatory?

A

Blocking cox reducesPG2 production which reduces production of prostanoids / pain-causing prostaglandins

48
Q

How does aspirin work as an anti-platelet?

A

cox acts via glycoprotein receptors which cause platelets to clump together
Inhibition means less production of intermediate thromboxane a2 (from arachidonic)= less platelet aggregation

49
Q

Example of protein mediators that can activate enzyme linked receptors

A

Growth factors, cytokines, hormones

50
Q

Activation of enzyme-linked receptors enables binding and activation of many Intracellular signalling properties which do what?

A

Lead to changes in Gene transcription and in many cellular function

51
Q

Characteristic of enzyme linked transmembrane receptors

A

-Large extracellcular binding domain
-Single transmembrane helical region

52
Q

Feature of Receptor tyrosine kinase family

A

Ligand binding causes receptor dimerisation
- get either transphosphorylation or autophosphophorylation within the receptor itself

53
Q

Activation of receptor serine/threonine kinase family does what?

A

Activation of these phosphorylates serine and threonine residues in target cytosolic proteins

54
Q

Feature of cytokine receptors I non-receptor tyrosine kinase family

A

Lack integral kinase activity but activate separate kinases associated with the receptor

55
Q

Feature of tyrosine phosphatase receptor family

A

Dephosphorylate tyrosines on other transmembrane receptors or cytoplasmic proteins, common in immune cells

56
Q

Function of receptor guanylyl cyclase family

A

Catalyse the formation of cGMP from GTP via a cytosolic domain

57
Q

Transduction mechanism for receptor tyrosine kinase

A

-Growth receptor binds to receptor domain(linked via alpha helix) which crosses over to a domain of the receptor (inside=tyrosine kinase)
- when growth factor binds in the active form, you get a conformational change which leads to dimerisation = starts auto/transphosphorylation of tyrosine kinase domains
- (intermediary) SH2-domain protein leads to a phosphorylation of it, the domain binding protein, when activates another protein called RAS which triggers a lot of steps

58
Q

What is imatinib?

A

Protein kinase inhibitor

59
Q

What is imatinib used for?

A

Used to increase years of those with chronic myelogenous leukaemia (CML)

60
Q

Mechanism of action for imatinib

A

Directly inhibits protein kinase itself
By inhibiting the kinase, it blocks any downstream signalling and improves the outcome for patients

61
Q

Everolimus (afinitor) used in treatment for?

A

Renal cell carcinoma (kidney cancer)

62
Q

What type of inhibitor is everolimus?

A

Pan kinase inhibitor

63
Q

Everolimus acts on what? And function?

A

Target of rapamycin (mTOR), which blocks the effect upon gene expression

64
Q

Mechanism of action for Janus kinase inhibitors

A

Compete with ATP for the ATP binding sites on the kinase, preventing activation

65
Q

JAK inhibitors = newest class of drugs to treat?

A

RA - rheumatoid arthritis

66
Q

Leptin receptors are found where? Activation can result in?

A

Hypothalamus
- result in behavioural esteets upon feeding behaviour

67
Q

Lepton used therapeutically for?

A

Losing weight in terms of obesity

68
Q

In the hypothalamus, lepton can act as a satiety signaller what does this mean?

A

Activating these receptors mean you don’t feel as hungry, knock off effect on eating behaviour

69
Q

Leptin is released from? What tissue?

A

Adipose tissue

70
Q

Lipodystrophy vs healthy person

A

Healthy person- normal levels- normal regulation
Lipodystrophy-Reduced numbers of adipose tissue- reduced levels of lepton- reduction in inhibition of eating behaviour

71
Q

Metrileptin (Recombinant form of leptin) function

A

Readdress the balance by stimulating more of these enzyme linked receptors

72
Q

Which of the following drugs is an irreversible enzyme inhibitor of the enzyme COX?
Captopril, aspirin, penicillin, sildenafil ,oseltamivir

A

Aspirin
- most drug examples: reversible inhibitors of enzymes except aspirin and penicillin but aspirin irreversibly inhibits the COX enzyme

73
Q

What is the function of dimerisation in kinase linked receptors?

A

Ennobles mutual autophosphorylation of tyrosine residues by tyrosine kinase

Pharmacodynamics (17 decks)

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