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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
Q

DNA cleavage agents

A

target: DNA
structure: variety
mechanism: cut DNA & destructively interact with backbone

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26
Q

enediynes: calicheamicin y1

A

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

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27
Q

enediynes: bleomycin

A

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

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28
Q

KM:

A

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

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29
Q

larger KM =

A

more substrate required for fast rate
or weaker binding affinity

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30
Q

Vmax

A

the maximum rate of reaction in the presence of saturating levels of substrate

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31
Q

KM/Vmax

A

a measure of the effective second order rate constant for an enzyme catalysed reaction

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32
Q

inhibitor

A

any molecule that acts to reduce the rate of an enzymatic reaction.

33
Q

reversible inhibitors

A
  • attach via non-covalent interactions
  • Generally don’t undergo chemical reaction whilst bound to the enzyme
  • Three common types
34
Q

Acalabrutinib type of drug and mechanism

A

Lymphoid malignancy drug
Mode of action: covalently inhibits Bruton tyrosine kinase

35
Q

Acalabrutinib repurposing

A

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
Q

Ebselen type of compound, drug and mechanism

A

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
Q

Ebselen trial data for SARS-CoV-2

A
  • 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
Q

EIDD-2801 [Sheahan et al., 2020] structure, mechanism

A
  • Structure: nucleoside analog.
  • Mode of action: incorporates into viral RNA chains leading to premature chain termination.
39
Q

EIDD-2801 [Sheahan et al., 2020] original target and repurposing data

A

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
Q

Faripivarir structure and mechanism

A
  • 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
Q

whats the benefits of faripivarir self-inhibiting its own metabolism

A

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
Q

faripivarir drug repurposing

A
  • 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
Q

Type 1 interferons structure and mechanism

A

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
Q

type 1 interferons drug repurposing

A

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
Q

remdesivir structure and mechanism

A
  • Structure: nucleoside analog.
  • Mode of action: incorporates into viral RNA chains leading to premature chain termination. [Saul & Einav, 2020]
46
Q

remdesivir original use and repurposing

A

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
Q

RECOVERY trial hydrochloroquinone

A

decreased the likelihood of discharge after 28 days

48
Q

RECOVERY trial lopinavir

A

no effect

49
Q

lopinavir [Cao et al., 2020] study for SARS-CoV-2

A

no significant effect on mortality or viral load

50
Q

RECOVERY trial dexamethasone

A

decreased death by ~35% in ventilated patients
decreased death by 20% in patients receiving O2
no effect on patients not receiving either

51
Q

dexamethasone

A

orally active glucocorticoid used as topical steroid
cheap
antinflammatory
[Intro to Med Chem, P.L. Graham, 2017]

52
Q

tocilizumab RECOVERY trial

A

improved survival and other clinical outcomes regardless of extent of respiratory support

53
Q

tocilizumab and sarilumab
how could they target COVID?

A

mAb antagonists
target interleukin 6
increased covid severity is associated with increased proinflammatory cytokines [Lescure MD et al., 2021]

54
Q

tocilizumab REMAP-CAP study

A

decreased mortality by 8% for patients in intensive care

55
Q

sarilumab Phase III trials

A

showed no significant efficacy in patients receiving O2 [Lescure MD, et al., 2021]

56
Q

Pfizer-BioNTech vaccine

A
  • 2 x0.3 mL doses 3 weeks apart
  • lipid nanoparticle delivery
  • full length spike protein code
57
Q

Oxford Astra-Zeneca

A
  • 2x 0.5 mL doses 4-12 weeks apart
  • full length spike protein code
58
Q

WHO SOLIDARITY trial EC50 Remdesivir

A

0.77 uM

59
Q

Sofosbuvir Zika

A

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
Q

remdesivir Ec50 against Ebola

A

0.003-0.009 uM

61
Q

favipiravir ebola

A

RNA polymerase inhibitor
simple purine nucleic acid analog
[Hassanipour, et al., 2021]

62
Q

favipiravir ebola [Guedj et al., 2018] study

A

plasma above [70-80 ug/mL] showed significantly reduced viral load, infectivity and extended survival

63
Q

Ervebo 2019 vaccine

A

100% effective prevention
single dose
live attenuated virus

64
Q

5 integrase strand transfer inhibitors

A

netropsin
raltegravir
dolvegravir
carbotegravir
elvitigravir

65
Q

[Zhao et al., 2022] core structure of integrase strand transfer inhibitors

A

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
Q

[Zhao et al., 2022] preferential binding of INSTIs

A

preferentially bind to the active site of integrase within the intasome rather than free integrase

67
Q

[Zhao et al., 2022] give the common resistance mutations against Raltegravir

A

Y143H/R/C hydrophobic to charged
Q148H/R/K polar uncharged to charged

68
Q

azidothymidine

A

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
Q

lamivudine [Kumar MD et al., 2009] trial

A

long intracellular half-life = 1-2 daily doses
one of the more tolerable
preferred for initial or subsequent combo therapy

70
Q

lamivudine [The Comprehensive Pharmacology Reference, Weston, 2007]

A

prodrug (phosphate group would prevent diffusion across membranes)
cytidine analog NRTI
orally bioavailible
weak inhibitor of host DNA polymerase

71
Q

2 NRTIs with a once daily dose [Rosenbach et al., 2002]

A

didanosine and efavirenz

72
Q

Hydroxythylamine

A

protease inhibitor: transition state isostere
OH mimics TS OH + binds -> Asp of HIV protease
R config preferred

73
Q

protease inhibitor discovered through HTS

A

tipranavir
saved many lives as used as combo with ritonavir for patients with resistant mutations

74
Q

efavirenz SAR [Bastos et al., 2016]

A

CF3 essential as it improves potency by lowering the pKa, -> better HB to enzyme
swapping C6 Cl to nitro gives 2x activity

75
Q

NNRTI developed through random screening

A

nevapirine

76
Q

saquinavir [Invirase, Roche, 2007]

A

peptide-like analogue
binds to Asp of HIV protease active site
taken with ritonavir
Ec50 = 1-30 nM

77
Q

HIV protease mutations associated with decreased susceptibility to saquinavir

A

G48V more hydrophobic
L90M added SMe

78
Q

2 subtypes of penicillins

A

aminopenicillins (amoxicillin)
carboxypenicillin (carbenicillin)

79
Q

amoxicillin SAR

A

EWD amino group makes = acid-stable

BIO3041 medchem (3 decks)

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