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BIO3041 medchem > drug bank > Flashcards

drug bank Flashcards

1
Q

magainins drug class

A

target: bacterial cell membranes
structure: 15 aa peptide; coils into hydrophobic helices
mechanism:
- helices associate to hydrophilic phospholipid head
- causes membrane to bend back on itself
- pore stabilized by constant association
extracted from: african clawed frog
examples: pexigan for infected diabetic foot ulcers, failed phase III [Gen, 2016]

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2
Q

amphotericin B

A

target: fungal sterol ergesterol
binds other sterols inc. cholesterol (side effects)
structure: looped amphoteric
hydrophobic = repeated transalkenes
hydrophilic = polar OH, important for binding
mechanism:
- binds ergesterol and forms polar pore
- 6 Ab + 6 erg = pore
- leaky cell = dead
extracted from: S. nodosus

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3
Q

valinomycin

A

target: [potassium] in cell (passes through cell membrane)
structure: micelle-like
hydrophobic outside = side chains of valine and hydroxyisovalerate
hydrophilic inside = polar carbonyl oxygens of the ester and amide groups
mechanism: slots into membrane via hydrophobic interactions and forms pore
ion carrier, inverted detergent
extracted from: streptomyces

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4
Q

gramicidin A

A

target: bacterial cell wall
structure: 15 aa peptide forms hydrophobic helical dimers
mechanism:
- dimers slot into membrane via hydrophobic interactions and form K+ pore
- dimers long enough to span membrane
extracted from: B. brevis

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5
Q

other examples of antibacterial ion carriers like valinomycin

A

nigericin, monensin A, and lasalocid
used veterinary medicine to control bacterial count in cattle rumen and poultry intestines

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6
Q

why does a leaky cell = dead cell

A

ion gradient and potentials of cell ruined

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7
Q

DNA groove binder general modes of action

A
  1. reversible inhibition of DNA-dependent function
  2. irreversible damage to DNA
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8
Q

distamycin & netropsin

A

DNA groove binders
target: AT rich minor grooves
structure: curved because of ox. states of atoms
- curved structure mimics DNA curve so interactions are stronger
mechanism: bind to minor groove
- alter conformation of DNA inhibiting trans/rep

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9
Q

intercalators general mode of action

A

slide between bases of same strand
prevents trans/rep by inhibiting enzyme binding and distorting structure of helix

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10
Q

intercalators general structure

A

must have planar/aromatic region to fit between bases and form VdW
can have polar groups (+ve) that form ionic bonds with -ve backbone and improve binding

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11
Q

3 types of intercalators

A

anthrocyclines
aminoacridines
actinomycins

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12
Q

anthrocyclines

A

target: poison topoisomerase II
structure: intercalator structure
mechanism:
- stabilises topoisomerase-DNA complex preventing trans/rep
- antitumor, will target rapidly proliferating cells more
examples:
doxorubicin - aminosugar interacts with backbone
mitoxantrone - prefers GC rich minor groove

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13
Q

actinomycins: dactinomycin

A

target: DNA bases
structure:
- cyclic pentapeptides form H bonds with backbone
mechanism: general intercalator mechanism

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14
Q

aminoacridines: proflavine

A

target: DNA bases
structure:
- ionized at pH 7
- flat tricyclic ring
mechanism:
- aminium ions bond ionically to backbone
- in presence of light can cause ds break in DNA
other examples: amsacrine- leukaemia

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15
Q

types of alkylating agents

A

nitrogen mustards
ethyleneimines
methanosulfates
Pt complexes

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16
Q

nitrogen mustards:

A

target: guanine N7 or adenine N3
structure: N-R, bound to 2x Cl
mechanism: anchimeric assistance
nitrogen atom displaces a chloride
intramolecularly to form highly electrophilic aziridinium ion. Alkylation of DNA occurs. As the process can be repeated, cross-linking between chains or within the one chain will occur.
examples:
cyclophosphamine prodrug - analogue of chlormethine improved selectivity
estramustine - estrogen analogue so passes through membranes
mechlorothamine - simplest, least selective not used

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17
Q

alkylating agents

A

target: nucleophiles
- strongest Nu in DNA: guanine N7 or adenine N3
structure: variety
mechanism: form covalent bonds with bases, preventing trans/rep

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18
Q

how has chlormethine been altered to make cyclophosphamide

A
  • substituted ring added
  • phosphoramide group
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19
Q

how is cyclophosphamide prodrug metabolised and how is it more selective

A
  • cytochrome p450 oxidises ring
  • followed by non-enzymatic hydrolysis
  • more selective for stronger nucleophiles (i.e. DNA) as N tempered by phosphoramide group
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20
Q

Pt complexes

A

alkylating agents
target: guanine N7 or adenine N3
structure:
cis planar Pt complex
mechanism:
- strong Pt-N formed
- intrastrand crosslinking bc of cis config.
- unwinding prevents trans/rep
- unwinding due to crosslinks interfering with H bonds between strands
examples: cisplatin

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21
Q

Pt complexes cisplatin

A

alkylating agent
target: guanine N7 or adenine N3
structure:
- net 0 charge, crosses membrane
- cis planar Pt complex
- 2 amine, 2 Cl
mechanism:
- 2x Cl ligands replaced by water then N of base

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22
Q

ethyleneimines

A

alkylating agents
target: guanine N7 or adenine N3
structure:
- preformed arizidines like Nmustards
- no +ve charge
mechanism: SN2
arizidinium ion displaces the two amine groups and binds covalently to nucleophilic sites on DNA bases. can bind twice to adjacent bases on same strand or to each base of a base pair across both strands.

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23
Q

ethyleneimines: diaziquone

A

alkylating agents
target: guanine N7 or adenine N3, brain tumors
structure:
- lipophilic, crosses BBB
- heterocyclic aromatic core
- N=N
- reaches peak conc in 1 hour
- steep dose-response relationship
mechanism: similiar to Nmustard

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24
Q

methanosulfonates

A

alkylating agents
target: guanine N7 or adenine N3
structure:
- 2Me-S form intrastrand crosslinks
- unwinding prevents trans/rep
mechanism:
- alkylate gN7 or aN3 by SN2
examples: busulfan- anticancer
treosulfan - prodrug for bone marrow recipients

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25
DNA cleavage agents
target: DNA structure: variety mechanism: cut DNA & destructively interact with backbone
26
enediynes: calicheamicin y1
DNA cleavage agents target: DNA structure: pro-drug - formation of active aromatic ring - nucleophilic attack on prodrug - followed by bergman cyclisation mechanism: - metabolism of prodrug produces diradical species - diradical abstracts 2H and DNA becomes diradical - later reactions with O2 leads to chain cutting other examples: esperamicin A1
27
enediynes: bleomycin
DNA cleavage agents target: DNA structure: - intercalator flat aromatic rings = VdW with bases metal binding domain = N and imidazole ring ligate Fe2+ mechanism: - ligated Fe2+ reacts with O2 to form radicals - radicals formed in proximity to DNA (intercalation) so backbone cleaved
28
KM:
a measure of the substrate concentration required for significant catalysis to occur a measure of the strength of the ES complex, high KM indicates weak binding
29
larger KM =
more substrate required for fast rate or weaker binding affinity
30
Vmax
the maximum rate of reaction in the presence of saturating levels of substrate
31
KM/Vmax
a measure of the effective second order rate constant for an enzyme catalysed reaction
32
inhibitor
any molecule that acts to reduce the rate of an enzymatic reaction.
33
reversible inhibitors
- attach via non-covalent interactions - Generally don’t undergo chemical reaction whilst bound to the enzyme - Three common types
34
Acalabrutinib type of drug and mechanism
Lymphoid malignancy drug Mode of action: covalently inhibits Bruton tyrosine kinase
35
Acalabrutinib repurposing
Off-label use for 19 patients with severe COVID-19 respiratory distress and levels of the inflammatory markers C-reactive protein and IL-6. [Roschewski 2020]
36
Ebselen type of compound, drug and mechanism
Organoselenium compound NP Mode of action: Pleiotropic. Mimics glutathione peroxidase (antioxidant defence). Very reactive with protein thiols so inhibits proteins reliant on cysteine such as viral proteases. Inhibition reversed by adding reducing agents. [Azad & Tomar, 2014]
37
Ebselen trial data for SARS-CoV-2
* HTS of a large library of compounds, strongest inhibitory activity against SARS-CoV-2 protease. IC50 = 0.67 uM. [Jin et al., 2020] * No toxicity at high doses across multiple clinical trials.
38
EIDD-2801 [Sheahan et al., 2020] structure, mechanism
* Structure: nucleoside analog. * Mode of action: incorporates into viral RNA chains leading to premature chain termination.
39
EIDD-2801 [Sheahan et al., 2020] original target and repurposing data
original target viral RNA repurposing: * with Remdesivir inhibits SARS-CoV-2 in human epithelia and several coronaviruses in mice. Extent of inhibition is dose-dependent. o Viral strains resistant to Remdesivir are more sensitive to EIDD-2801. o Increases rates of mutation, particularly in MERS-CoV: A>G and C>U mutations.
40
Faripivarir structure and mechanism
* Structure: guanine nucleoside analog prodrug * Mode of action: nucleoside analog which competes with endogenous nucleotides for viral RNA polymerase. incorporation leads to disruption of replication and transcription [Du & Chen, 2020]
41
whats the benefits of faripivarir self-inhibiting its own metabolism
o Self-inhibits its metabolism extending plasma half-life, and increasing plasma parent: inactive metabolite which drives increased cellular uptake. This compensates for high SARS-CoV EC50. [Du & Chen, 2020]
42
faripivarir drug repurposing
* Broad spectrum viral polymerase inhibitor approved for influenza A. * Protected 100% of mice against ebola and in humans a retrospective analysis showed it reduced viral load during an outbreak 2014-2015. [Oestereich et al., 2015] [Bai et al., 2016]
43
Type 1 interferons structure and mechanism
target: HIV, stimulates immune components structure: cytokines (helical proteins) mode of action: bind a cell surface receptor to initiate an intracellular signal cascade leading to changes in gene expression commonly activate JAK-STAT pathways
44
type 1 interferons drug repurposing
approved for hepatitis B and C repurposing: * Uncontrolled preliminary study of COVID-19 patients corticosteroids and IFN 1 accelerated resolution of lung abnormalities and improved oxygen saturation significantly better than just corticosteroids. [Zhou 2020] * Animal testing showed IFN 1 was protective and SARS and MERS-CoV. [Barnard 2006]
45
remdesivir structure and mechanism
* Structure: nucleoside analog. * Mode of action: incorporates into viral RNA chains leading to premature chain termination. [Saul & Einav, 2020]
46
remdesivir original use and repurposing
approved for ebola repurposing: * Showed promising results against SARS-CoV-2: o Human airway epithelial cells: remdesivir prevented SARS- and MERS-CoV replication. This was dose-dependent, >0.05 uM [Sheahan et al., 2017] * Remdesivir was removed as option for testing as it was shown to increase mortality rates. 2 lines of monoclonal antibodies showed significantly better activity. [Mulangu et al., 2019]
47
RECOVERY trial hydrochloroquinone
decreased the likelihood of discharge after 28 days
48
RECOVERY trial lopinavir
no effect
49
lopinavir [Cao et al., 2020] study for SARS-CoV-2
no significant effect on mortality or viral load
50
RECOVERY trial dexamethasone
decreased death by ~35% in ventilated patients decreased death by 20% in patients receiving O2 no effect on patients not receiving either
51
dexamethasone
orally active glucocorticoid used as topical steroid cheap antinflammatory [Intro to Med Chem, P.L. Graham, 2017]
52
tocilizumab RECOVERY trial
improved survival and other clinical outcomes regardless of extent of respiratory support
53
tocilizumab and sarilumab how could they target COVID?
mAb antagonists target interleukin 6 increased covid severity is associated with increased proinflammatory cytokines [Lescure MD et al., 2021]
54
tocilizumab REMAP-CAP study
decreased mortality by 8% for patients in intensive care
55
sarilumab Phase III trials
showed no significant efficacy in patients receiving O2 [Lescure MD, et al., 2021]
56
Pfizer-BioNTech vaccine
- 2 x0.3 mL doses 3 weeks apart - lipid nanoparticle delivery - full length spike protein code
57
Oxford Astra-Zeneca
- 2x 0.5 mL doses 4-12 weeks apart - full length spike protein code
58
WHO SOLIDARITY trial EC50 Remdesivir
0.77 uM
59
Sofosbuvir Zika
RNA polymerase inhibitor approved for Hepatitis C uridine analog, phosphate group, 2 aromatic rings, fluorine Protective in mice significant inhibition of Zika in human cancer cell lines [Bullard-Feibelman et al., 2017]
60
remdesivir Ec50 against Ebola
0.003-0.009 uM
61
favipiravir ebola
RNA polymerase inhibitor simple purine nucleic acid analog [Hassanipour, et al., 2021]
62
favipiravir ebola [Guedj et al., 2018] study
plasma above [70-80 ug/mL] showed significantly reduced viral load, infectivity and extended survival
63
Ervebo 2019 vaccine
100% effective prevention single dose live attenuated virus
64
5 integrase strand transfer inhibitors
netropsin raltegravir dolvegravir carbotegravir elvitigravir
65
[Zhao et al., 2022] core structure of integrase strand transfer inhibitors
metal chelating scaffold binding 2 Mg2+ cofactors halogenated benzene side chain that intercalates with viral DNA flexible linker connects core scaffold to halobenzyl side chain
66
[Zhao et al., 2022] preferential binding of INSTIs
preferentially bind to the active site of integrase within the intasome rather than free integrase
67
[Zhao et al., 2022] give the common resistance mutations against Raltegravir
Y143H/R/C hydrophobic to charged Q148H/R/K polar uncharged to charged
68
azidothymidine
prodrug (charged phosphate group would prevent diffusion across membrane) deoxythymidine analog NRTI first anti-HIV drug approved by FDA competitive inhibition of reverse transcription resulting in chain termination (no 3'OH) high affinity to DNA polymerase, -> toxic side effects
69
lamivudine [Kumar MD et al., 2009] trial
long intracellular half-life = 1-2 daily doses one of the more tolerable preferred for initial or subsequent combo therapy
70
lamivudine [The Comprehensive Pharmacology Reference, Weston, 2007]
prodrug (phosphate group would prevent diffusion across membranes) cytidine analog NRTI orally bioavailible weak inhibitor of host DNA polymerase
71
2 NRTIs with a once daily dose [Rosenbach et al., 2002]
didanosine and efavirenz
72
Hydroxythylamine
protease inhibitor: transition state isostere OH mimics TS OH + binds -> Asp of HIV protease R config preferred
73
protease inhibitor discovered through HTS
tipranavir saved many lives as used as combo with ritonavir for patients with resistant mutations
74
efavirenz SAR [Bastos et al., 2016]
CF3 essential as it improves potency by lowering the pKa, -> better HB to enzyme swapping C6 Cl to nitro gives 2x activity
75
NNRTI developed through random screening
nevapirine
76
saquinavir [Invirase, Roche, 2007]
peptide-like analogue binds to Asp of HIV protease active site taken with ritonavir Ec50 = 1-30 nM
77
HIV protease mutations associated with decreased susceptibility to saquinavir
G48V more hydrophobic L90M added SMe
78
2 subtypes of penicillins
aminopenicillins (amoxicillin) carboxypenicillin (carbenicillin)
79
amoxicillin SAR
EWD amino group makes = acid-stable

BIO3041 medchem (3 decks)

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