Drug Targets Flashcards
1
Q
What is the study of carbohydrates?
A
Glycomics
2
Q
What is the general structure of carbohydrates?
A
Cn H2n On
3
Q
What does L mean in a carbohydrate name?
A
L means that the OH group neighbouring the terminal group is on the left in Fisher projections
4
Q
How are hemiacetals and hemiketals formed?
A
Carbohydrates undergo ring closure spontaneously and reversibly in water
5
Q
How is a disaccharide formed?
A
2 monosaccharides undergo condensation reaction to form a disaccharide
6
Q
How are sugar moieties linked?
A
An acetal forms at the anomeric carbon and the link between sugar moieties is known as a glycosidic bond
7
Q
What are the main cellular roles of carbohydrates?
A
Energy storage and structural
Cell recognition, cell regulation and cell growth
8
Q
How is cell recognition carried out?
A
By glycoconjugates
9
Q
Examples of glycoconjugates
A
Sugars linked to proteins (glycoproteins) or lipids (glycolipids)
10
Q
How do new drugs help with autoimmune diseases?
A
New drugs are designed to interact with carbohydrates that are in the structure of cell surface and alter cell recognition and regulating processes
11
Q
How do glycoconjugates work?
A
The lipid or protein is bound to the cell membrane and the carbohydrate is freely accessible in the aqueous environment as it is highly polar (OH groups)
12
Q
Why are carbohydrates good tags?
A
Number of structural variants
13
Q
If a carbohydrate has 2 glucose molecules, how many disaccharide products can it make?
A
11
14
Q
What are the 3 types of glycoproteins?
A
N-linked, O-linked and Non-enzymatic glycoproteins
15
Q
What is the structure of N-linked glycoproteins?
A
Saccharide attached to N of asparagine in polypeptide chain
16
Q
How are sugar molecules attached to N-linked glycoproteins?
A
Sugar molecule is a complex multi-chained molecule called a glycan
17
Q
What do N-linked glycoproteins dictate?
A
Migration pattern of immune cells they are bound to
18
Q
What identifies between self and non-self?
A
N-linked glycoproteins
19
Q
What is the structure of O-linked glycoproteins?
A
Saccharide molecule added as single sugars to hydroxyl side chain of serine and threonine
20
Q
Why are O-linked glycoproteins important in cells?
A
Important in cellular function and influence the immunological recognition of antigens and their signal transduction
21
Q
What do O-linked glycoproteins help process?
A
Process and expression of other glycoproteins
22
Q
How are non-enzymatic glycoproteins formed?
A
Form when polypeptides have sugars added to them over time
23
Q
When are non-enzymatic glycoproteins in high production?
A
In those with excess blood glucose as sugar binds to haemoglobin
24
Q
Which test measures excess production of non-enzymatic glycoproteins?
A
A1C test
25
Why might non-enzymatic glycoproteins change the proteins they are bound to?
Hydrophilic and polar characteristics
26
How are lipids attached to carbohydrates in glycolipids?
Covalent bonds
27
Where are glycolipids found?
On the surface of all eukaryotic cell membranes and extend out from the phospholipid bilayer
28
What are the most common glycolipids in cell membrane?
Glycerolipids and sphingolipids
29
How does the sugar moiety attach to glycolipids?
Sugar moiety attaches to the polar head group outside the cell
Attachment usually occurs between the anomeric carbon of sugar and the free hydroxyl group on the lipid backbone
30
What do glycolipids dictate?
Blood type - depending on the sugars attached to them
31
What do oligosaccharides do?
Bind to a specific glycolipid on the surface of red blood cells and act as an antigen
They also provide energy to the cells and assist the immune system by eliminating pathogens from the body
32
What percentage of the outer layer of plasma membranes are glycolipids?
3%
33
What are the 4 types of glycosphingolipids?
Neutral, basic, acidic and amphoteric
34
What are glycoglycerolipids associated with?
Photosynthetic membranes
35
What are antigens?
Molecules, moieties, foreign particles or allergens that can bind to a specific antibody
36
What forms can antigens be in?
Proteins, carbohydrates, lipids or nucleic acids
37
How can antigens be labelled?
Self for own body antigens and non-self for viruses and bacteria
38
What is the mechanism of antigens and antibodies known as?
Antibody is the paratope and antigen is the epitope
39
What happens when antibodies and antigens bind?
Immune response triggered aimed at destroying the invader
40
What shape are antibodies?
Y shaped
41
What are antibodies made of?
Y arms are made of 2 heavy and 4 light peptide chains
42
Where is the variable region of antibody?
At the N-terminal of the light chain there is a highly variable region of roughly 110 amino acids
43
How do antibodies differ?
The variable region differed and gives the selectivity of antibodies
44
Where are antibodies produced?
B lymphocytes
45
Issues with using mice antibodies
Human body had adverse reaction known as the HAMA (Human anti-mouse/anti-murine response)
46
What happened in HAMA response?
Antibodies are generated to counter mouse antibodies and can cause symptoms from rash to kidney failure
47
% of chimeric antibodies
66% human and 33% mouse
48
% of humanised antibodies
90% human and 10% human
49
What are the fixed domains in chimeric antibodies?
Human fixed domains
50
What is the complimentary determining region?
The site where the antibody binds to the antigen through recognition and is extremely specific
51
What are enzymes?
Biological catalysts
52
How are enzymes denatured?
Enzymes are very sensitive to conditions so if temperature or pH goes outside correct range enzyme is denatured
53
Action of reversible inhibitor?
Inhibitors fit the active site and bind more strongly than the natural substrate and prevent enzymatic reactions
54
What happens as concentration of reversible inhibitors increases?
Inhibition increases
55
What happens to the action of reversible inhibitors as concentration of substrate increases?
Inhibition will be less effective
56
What type of competitors are statins?
Competitive/reversible inhibitors
57
What enzyme do statins interact with?
HMGR enzyme
58
Why do statins have more enhanced binding than natural substrate?
Enhanced binding due to extra hydrophobic interactions with the enzyme
59
Why are irreversible inhibitors not reversible?
Irreversible inhibitors form covalent bond with amino acids in an enzyme and permanently block them
60
What do the most effective inhibitors contain?
Electrophilic functional groups that can interact with a nucleophilic group in the amino side chain
61
Why are irreversible inhibitors toxic?
They are highly reactive and can covalently link to a different protein or nucleic acid and trigger an unfavourable immune response
62
Why are irreversible inhibitors not sensitive to concentration?
Since the inhibitor cannot be removed due to covalent bonding
63
What is Disulfiram used for?
To treat alcoholism
64
What enzyme does disulfiram affect?
Aldehyde dehydrogenase
65
What are allosteric binding sites?
Binding sites which are separate from the active site
66
Allosteric feedback
Allosteric inhibitors can be used to stop the production of a material by inhibiting the first enzyme in a biosynthetic pathway
67
What type of inhibitor is 6-Mercaptopurine?
Allosteric, reversible and inhibits the first enzyme in the biosynthetic pathway
68
What is the action of 6-Mercaptopurine?
Inhibits the formation of purine nucleotides, adenine and guanine, and so the synthesis of DNA and RNA are also blocked
Leads to death of rapidly proliferating cells, particularly malignant ones
69
Action of uncompetitive inhibitor
Binds reversibly to an enzyme which has the substrate already bound to the active site
70
What is level of inhibition of uncompetitive inhibitors dependent on?
Sufficient substrate presence
71
When are uncompetitive inhibitors likely to be used?
For reactions with two or more substrates or products
72
Action of non-competitive inhibitors
Bind to allosteric binding site to inhibit a reaction without affecting the strength of substrate binding
Allosteric binding distorts the active site so that the catalytic process is disrupted but not substrate binding
73
What is mixed inhibition?
Active site distortion will change the catalytic process and the substrate binding
74
What are transition state analogues?
Inhibitors that act almost as irreversible inhibitors but use non-covalent process
Drug is designed to mimic the transition state of the catalysed reaction
75
How do renin inhibitors work?
Renin inhibitors will lower blood pressure by preventing the formation of angiotensin II
76
What is renin responsible for?
Protease enzyme responsible for the cleavage of angiotensin to angiotensin I, which is further converted to angiotensin II
77
What does renin contain in the active site?
2 aspartyl residues and bridging water molecules
78
79
How do suicide inhibitors work?
They appear similar to the substrate to allow it to access the active site.
Drug is transformed at the active site to allow it to covalently bond to the enzyme
80
Why are suicide inhibitors highly selective?
The inhibitor is only generated at the active site
81
What does B-lactamose do?
B-lactamose enzyme catalyses the hydrolysis of the penicillin lactam ring
82
What can suicide inhibitors be use for?
Suicide inhibitors can also be used for labelling specific enzymes for diagnostic purposes.
83
What are isozymes?
Enzymes which differ in the sequence of their amino acids but can still catalyse the same reaction
84
How do isozymes differ?
They work at different catalytic efficiencies
They work at different pHs, temperatures and salinities so can work in different systems/tissues
85
How many isozymes are possible for an enzyme synthesised from 2 different amino acids?
5
86
What can subunits of Lactate Dehydrogenase (LDH) be tagged with?
H and M
HHHH HHHM HHMM HMMM MMMM
87
Where in the body are subunits of LDH tagged with H?
Heart muscle
88
Where in the body are subunits of LDH tagged with M?
Skeletal muscle
89
How does Indometacin work?
In Rheumatoid arthritis, COX-2 is activated and produces excess prostaglandins
Indometacin inhibits enzyme and reduces prostaglandin levels to reduce disease symptoms
90
What are the negatives of Indometacin?
Can also inhibit formation of beneficial prostaglandins in GI tract and kidneys
91
What differs between COX-1 and COX-2?
COX-2 has an extra side pocket in the active site as it has valine group
COX-1 has a isoleucine group which is bulkier than valine
92
Why is targeting isozymes important?
Leads to less sides effects as well as more selective and effective drugs
93
What are the isozymes of Monoamide Oxidase?
MAO-A and MAO-B
94
What does MAO-A do?
Selective for the breakdown of serotonin and catalysing the breakdown of noradrenaline to 3,4 dihydroxymandelic acid
95
What do MOA-A inhibitors do?
Act as anti-depressants by preventing breakdown of MAO neurotransmitters
96
How do DNA and RNA differ?
RNA contains Uracil instead of Thymine
97
What is the structure of DNA?
Right-handed helix called β-helix
Helix makes a complete turn every 10 base pairs and have 2 principal grooves
98
Why are there minor and major grooves in DNA?
Helices are not perfectly out of phase so minor grooves form where the sugar-phosphate backbones are close together and major grooves are when they are further apart
99
What is the strand orientation of DNA?
5' to 3' orientation - the carbon in the deoxyribose sugar molecule that the phosphate group binds to
100
What are intercalating drugs?
Contain planar or heteroaromatic features which slip between base pairs layers of the DNA double helix
101
What groove do intercalating drugs preferentially approach?
Major groove
102
Why is intercalating reversible?
The drugs bind intermolecularly rather than covalently
103
Why is intercalation process thermodynamically favourable?
Due to positive entropy contribution associated with the disruption of the organised shell of water molecules around the ligands
104
How is binding of intercalating drugs enhanced?
By including ionised groups which can interact with the charged phosphate groups of DNA backbone
105
How does intercalating lead to cell death?
Range of processes take place which can prevent replication and transcription
106
What is proflavine?
An aminoacridine which can interact directly with bacterial DNA
107
What shape are groove-binding drugs?
Crescent shaped
108
How do groove-binding drugs interact?
Take part in intermolecular interactions with the edges of base pairs within the grooves of DNA
109
What are common groove-binding features?
Having a positive charge and aromatic rings linked instead of fused
110
Why do groove-binding drugs target the minor groove?
Minor groove is relatively devoid of molecules and drugs can favourably fill the void space
111
Why do Distamycin and Netropsin favourably interact with AT rich regions of DNA?
The 2-amino group of G sterically hinders distamycin and netropsin from binding to the minor groove of DNA where there is a prevalence of GC base pairs.
112
How do Distamycin and Netropsin interact with DNA?
Through H-bonding and hydrophobic interactions which locally displace structural water molecules along the spine of hydration which surrounds DNA
113
Where does electrostatic DNA binding occur?
Between cations and the anionic phosphate group of the exterior backbone
114
What happens once a molecule is electrostatically bound to DNA?
It can slide along the backbone to a specific binding site
115
What is the search for drug's most favourable binding site know as?
One-dimensional random walk
116
Why is sliding of electrostatically bound drugs important?
It allows drugs with multiple functionalities to transfer between binding sites
117
What is protein sliding?
Protein undergoes linear diffusion along the DNA helix
The molecule can move between non-specific binding sites
118
How does the protein find the specific DNA sequence required?
The protein binds to a random site and translocates to find the specific DNA sequence using trial and error
119
What is protein hopping?
When the protein is able to jump from the DNA and then rebind at a different specific binding site after diffusion
120
What are alkylating agents?
Highly electrophilic compounds that react with nucleophiles in DNA to form strong covalent bonds
121
What are the 2 functions of alkylating agents?
Monofuctional if bound to 1 strand and bifuntional if bound to 2
122
Why are alkylating agents useful in cancer treatment?
They can disrupt replication and transcription, eventually causing cell death
123
Why can alkylating agents be toxic?
They can alkylate with any nucleophilic group so have poor selectivity
124
How do alkyalting agents bond?
2 groups that can form covalent bonds that are able to prevent the replication and transcription of DNA
125
What happens when G is alkylated?
It prefers to bind to T to form Enol guanine, rather than to C. This is miscoding and can lead to disruption of DNA function and structure
126
What is aquation?
When chlorine molecules are replaced by water ligands
127
What are lipids?
Fatty hydrophobic compounds that perform a variety of functions in the body
128
What do lipids do?
Help in moving or storing energy, absorbing hormones and making hormones
129
What is the purpose of drugs that interact with lipids?
To disrupt the lipid structure of the cell membrane
130
How do tunnelling molecules work?
The drug interacts with the lipids in cell membrane to build a tunnel
131
Why are tunnelling molecules special?
They are amphoteric
132
How to Amphotericin B molecules cluster?
With alkene chains (lipophilic) facing outwards and interacting with cell membrane
Hydroxyl groups face inwards to create a hydrophilic tunnel
133
What does a hydrophilic tunnel transport?
Monovalent contents of the cell
134
How does Amphotericin B make a tunnel?
In fungal molecules, ergosterol H-bonds to Amphotericin and helps to make the tunnel
135
Why is Amphotericin B specific?
It prefferentialy binds to ergosterol rather than cholestorl
136
Why is Amphotericin dose limited?
Relatively toxic due to binding with cholesterol, removing polar cell contents and leading to cell death
137
What do ion carriers allow?
Allows material to be transported through the cell membrane
138
What does Valinomycin contain?
3 L-valine molecules, 3 D-valine, 3 L-lactic acid and 3 D-hydroisovalerate
They are linked in an alternating sequence of amide and ester bonds around the ring
139
What is the structure of Valinomycin?
Doughnut style structure, with polar carbonyl group of esters and amides on the inside and hydrophobic side chain on the outside
140
Why is the structure of Valinomycin favourable?
The hydrophobic side chains interact with fatty lipid interior of cell by Van der Waals
141
Why is Valinomycin specific for K+?
Hydrated Na+ is too large to be accomodated by the central cavity of the drug and Na+ holds water strongly
142
How do membrane tethers act?
Drug is tethered to the cell membrane to interact more easily with molecular targets that are also tethered to the cell membrane
143
What is MitoQ?
An antioxidant prodrug
144
What is the action of MitoQ?
Hydrophobic group aids the drug's entry into the mitochondria membrane and tethers to the lipid bilayer
Quinone ring system is reduced to active quinol which can act as an antioxident to neutralise free radicals
