Eustaquio Flashcards
1
Q
What is the trade name of Captopril?
A
Capoten
2
Q
What is the indication of Captopril?
A
CV disorders, hypertension
3
Q
What is a side effect of Captopril?
A
Dry cough
4
Q
What is the drug class of Captopril?
A
ACE-I
5
Q
What is the enzyme class of Captopril?
A
hydrolase
6
Q
What type of hydrolase does Captopril fall under?
A
Matallo protease (Zince Portease)
7
Q
What is the Mechanistic class of Captopril?
A
Acid-base
8
Q
What is the trade name of Enalapril?
A
Vasotec
9
Q
What is the trade name of Lisinopril?
A
Prinivil
10
Q
What is the trade name of Indinavir?
A
Crixivan
11
Q
What is the drug class of Indinavir?
A
HIV protease
12
Q
What is phenotypic screening?
A
it is empirical approach. It relies on the phenotypic measures of responses. You don’t know what you are targeting but you know your desired outcome. Uses cell-based assays or animal models
13
Q
What is target based screening?
A
molecular approach. Hypothesis driven. Uses high throughput and biochemical assay using an isolated target.
14
Q
What is a structure-guided drug design?
A
Apart of target based screening. Done to improve hits and usually relays on a Crystal structure. Can be used to make the drug fit into the target perfectly.
High throughput + optimization
15
Q
What is competitive inhibitors?
A
a substrate that competes with the endogenous substrate. if you have excess of the substrate then you can reverse the inhibition.
16
Q
What is the difference between uncompetitive vs. noncompetitive inhibitors.
A
Uncompetitive inhibitors uniquely bind to the enzyme substrate complex
Noncompeptive not so picky so it can either bind to the enzyme or to the enzyme susbtrate complex.
BOTH do not compete with the substrate
17
Q
What is a protease?
A
an enzyme that breaks down proteins and peptides using water (hydrolases). Either uses covalent catalysis or acid-based catalysis
18
Q
Covalent catalysis involves?
A
Serine, Cysteine and Threonine
19
Q
Acid-base catalysis involves what?
A
metallo and aspartic acid
20
Q
What are substrate mimics?
A
They mimic the substrate and target the active site
21
Q
What are transition state mimics?
A
They mimic the transition site but cannot go on to complete the reaction
22
Q
What is an example of a substrate mimic?
A
ACE Captopril
23
Q
What is an example of transition state mimic?
A
Hiv protease
24
Q
What roles do zinc play in the hydrolysis mechanism?
A
- Makes carbonyl group more electrophilic
- Makes water more nucleophilic
- Stabilizes the carboxylate anion
25
Is zinc acting as a lewis acid or a lewis base?
Its acting as a lewis acid. It accepts an electron
26
Why is cleavage of an amide bond a difficult task?
The pair of nonbonded electrons in the nitrogen can delocalize into the the adjacent carbonyl group making the carbonyl group less electrophillic and resistant to hydrolysis.
27
What do all protease do?
They form a transition state called a tetrahedral intermediate
28
What is the different type of protease?
1. Convalent, Ser, Cys, and Theronine makes a convalent bond with the tetrahedral intermediate
2. Acid base involves metallo and aspartic acid making a non-covalent bind with the intermediate
29
Which of the ACE-I aren't prodrugs?
Captopril, Lisinopril
30
Which can bind more tightly to the enzyme? Transition state mimic or enzyme mimic?
Transition state mimic. It has the highest energy.
31
What do transition state mimics do?
Converts the short lived transition state to a stable thermodynamic state
32
What are lyases
Cleaves a chemical bond without using water or oxidation.
Catalyzes the addition or elimination of a small molecule
Equilibrium reaction that can go both ways
33
What is carbonic anhydrase?
It catalyzes the reversible rxns of co2 and water to bicarbonate and a proton . It drastically speeds up this process.
34
What is the importance of Carbonic anhydrase to human health?
1. Respiration
2. Bone resorption
3. Ionic balance in various tissues
35
What is CA the drug target for?
Glaucoma and edema
36
What is the normal function of CA?
H+ is excreted and bicarbonate is reabsorbed
37
How does Dozolamide treat glaucoma?
The majority of liquid in your eye is bicarbonate. Dozolamide will inhibit bicarbonate from being secreted = decreasing the ocular pressure
38
What is the Zinc Biochemistry?
1. Zinc as cofactors in enzymes
2. Structural, finger proteins
3. Regulation (control of cellular zinc)
39
What are CAs known as?
metalloenzymes ZINC
40
What are transferases?
They move a functional group from one molecule to another.
41
What is an example of a transferases?
kinases
42
How do transferases work?
They transfer a phosphate from atp to an alcohol group. Usually OH on serine, or theronine
43
What disease involve kinase action
Cancer
44
What is the cause of CML?
Too much granules and blast being made not enough WBC is being produced
45
What is the cause of of CML?
It is a genetic disorder causes by a chromosomal translocation.
46
What new chromosome dose CML make?
Philadelphia chromosome that has a fusion protein BCR-ABL
47
What is BCR-ABL?
a mutated version of a tyrosine kinase
48
What happens with BCR-ACL is mutated?
It is constantly on so granulocytes and blast proliferation ins uncontrolled ABL kinase cannot turn off
49
Why doesn't Gleevec have a lot of SE?
It is very selective. Only selective for ABL tyr kinase.
50
How does Gleevec work?
It binds near the activation loop and prevents ATP from binding. Therefore substrate cannot be P, locking it in the inactive position
51
Why was the second generation drug, Dasatinib invented?
To overcome the common resistance. But it does not overcome the Tyrosine to Isoleucine mutation.
52
What is a two-substrate enzyme mechanism?
Has two substrate involved: ATP and the substrate that is going to get the substrate group added onto it.
53
What are the two main types of two-substrate enzyme mechanisms?
1. ternary complex
| 2. ping-pong
54
What is the ternary complex mechanism?
```
Both substrate (atp and substrate to be p) will bind to the enzyme and there will be a direct transfer of phosphate group.
Random or ordered
```
55
What is the ping-pong mechanism?
Phosphate is given to the enzyme and then the enzyme gives the phosphate group to the substrate.
56
What do most protein kinases following?
Ternary complex mechanism
57
What is a common mutation that can occur with Gleevac? Or cancer resistance?
Threonine isoleucine mutation.
58
What is the Thr315I mutation?
Usually Thr forms a hydrogen bond with Gleevec, the drug. When Thr is mutated to ISO, there is no longer than hydrogen bond, therefore there is a lost of activity
59
How is dasatinib different from imatinib?
It does not block the activation loop
60
What did Ponatinib overcome?
1. Steric hinderance caused by Tyr315I
| 2. loss of h bond with T315I = LOSS OF ACTIVITY AND AFFINITY
61
What is different with the molecule of Ponatinib?
Triple bond making it very planar
62
Why does Ponatinib cause more SE?
Because it doesn't interact directly with the activation loop
63
Will we have Gleevec for every disease?
No. CML is one mutation affecting one protein. This makes treatment easier and more effective.
It is an inhibitor. Developing an inhibitor is easier than making a medication that reactivates a dysfunctional protein.This disease has the same variant
64
What is oxidoreductase?
Transfer of one electron from one molecule to another.
65
What does the genetic variants in aldehyde dehydrogenates will cause what?
flushing, servere hangovers
66
What is the purpose of cholesterol?
1. Required for the structural component of cell membranes
2. bile acids
3. steroid hormones
67
Where is cholesterol made?
Liver and our diet
68
Why must Cholesterol be carried by lipoprotein across the cell?
B/x it is lipophillic
69
What is the difference between LDL and HDL?
LDL- low density lipoprotein
HDL- high density lipoprotein
LDL- transports cholesterol to cells
HDL- transports cholesterol to the liver for removal
70
What does a high LDL causes?
heart angina
brain strokes
peripheral, leg pain when walking
71
What is the rate limiting step on cholesterol?
HMG-CoA reductase
72
What are intrinsically disordered regions?
Part of the molecule that are disabled. These disabled regions have high energy state and are able to inter convert between confirmations
73
What moieties do all statins have in common?
HMG-COA moieties
| Rigid hydrophobic group
74
What kind of inhibitors are HMG-CoA i?
Competitive substrate mimic
75
What would happen if you did not do screening first when designing statins?
It would be hard because statins are so flexible.
76
How is specificity and tight binding of inhibitors achieved?
Bulky groups
77
What is protein turnover?
The balance between protein synthesis and protein degradation``
78
Why is protein turnover important?
to maintain cellular activity
79
What are the two main pathways of protein turnover?
Lysosome
| Proteasome
80
What does protein turnover play a major role in?
Cell cycle, signal transduction, immunity, stress responsive
81
What are lysosomes?
They are small vesicles with acidic lumen. The pH inside is acidic and has a lot of acidic hydrolases
82
If Lysosomes are made of hydrolases, why doesn't it digest itself?
It has a polysaccharide coating that protects itself.
83
What is the coating called
Glycocalyx
84
What do lysosomes do?
They degrade and digestive materials taken up form outside and inside the cell.
1. autophagy
2. endocytosis
85
What is the process of autophagy?
1. Isolation membrane will engulf the cargo
2. Forms autophagosome
3. fuses with lysosomes
4. Degradation
86
What are the roles of Autophagy?
1. house keeping/ cellular homeostasis
2. starvation response
3. Cellular remodeling
4. Microbial infections
87
What is bulk autophagy?
It is induced by starvation and it is nonselective, will just engulf everything. Untargeted process
88
What is selective autophagy?
Ubquitin tagged
| cell structures are tagged. Will only degrade things if they are tagged
89
What are some implications of autophagy dysregulation?
1. Cancer
2. Neurodegeneration
3. myopathies
90
How does Chloroquine work?
increased the pH inside the lumen of lysosomes. Hydrolases work best at an acidic environment. SO THIS WILL INHIBIT AUTOPHAGY
91
What will happen if the pH is greater than the pkA?
Deprotonated
92
What will happen if the pH is lower than the pka?
protonated
93
What causes neurodegeneration?
toxic protein aggregates build up
94
What is lysosomal storage disease?
the accumulation of materials inside the lysosomes that doesn't get degraded. Usually be mutations in gene that contribute to lysosomal function
95
What is lysosomal storage disease mainly due to?
deficiency or mutation in lysosomal hydrolases
96
What is an oprhan drug?
It is a drug developed for rare conditions. Regulations aren't as strict
97
Are orphan drugs a cure for the condition?
no it will just slow the progression of the disease
98
What are the treatments for lysosomal storage disease?
1. Enzyme replacement therapy
2. substrate reduction therapy
3. Chaperone therapy
99
What are enzyme replacement therapy?
give your cells hydrolases. Add tag to them so they can localize to your lysosome. Reduces storage materials
100
What are some disadvantage of ERT?
1. Has to be given as an IV
2. Some people can't be reached through the systemic circulation such as bone or brain
3. immune response to it
101
What is substrate reduction therapy
to slow down the production of storage materials instead of degrading it
102
What are some advantage of substrate reduction therapy?
1. can take it orally
2. do not generate immune response
3. small so it can cross the blood brain barrier
103
What are some disadvantage of substrate reduction therapy?
it is only available for two storage disorders
104
What do Chaperones help do?
Help fold proteins to their appropriate confirmation
105
What are some advantage of Chaperone therapy?
1. Can be taken orally
2. don not generate immune reactions
3. Potential to cross the BBB
106
What are some disadvantage of chaperone therapy?
some mutations are unresponsive
107
What makes lysosomal strorage disorders an excellent candidate for gene therapy?
single gene disorder well characterized
108
What kind of proteins do lysosome degrade>
long lived proteins
109
What kind of proteins do proteasome degrade?
short lived proteins. it must first be tagged by UB then it can be put into the barrol to be eaten up
110
How does UB attach to a substrate?
terminal of lys and forming and isopeptide bind with it
111
What are the three enzymes required for tagging?
1. E1 activation
2. E2 conjugation
3. E3 ligation
112
What determines if the tagged protein goes to proteasome or autophagy?
The number of ub that is attached. It makes a code and a specific UBD will bind to the coded ub.
113
What controls what gets in or out of the proteasome?
the regulatory cap. It recognizing only tagged proteins. It is the gate keeper
114
What can pass through the lipid bilayer
gas, small, unchanged
115
What are ion channels?
A collection of protein domains that together create a water filled pore to allow the passage of ion in responses to a chemical, temperature or mechanical stimuli.
116
What do ion channels do?
Use excitable cells to convert mechanical and chemical signals to electrical signals
117
What are excitable cells?
neuron, muscles and touch receptors
