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Biochemistry II > drug discovery > Flashcards

drug discovery Flashcards

1
Q

serendipity example

A

penicillin beta-lactam inhibits transpeptidase of peptidoglycan synthesis

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2
Q

how can genetic differences modulate drug efficacy

A

beta blockers on beta-1 adrenergic receptor
different alleles = different effects
AA changes

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3
Q

what can be designed to target an enzyme

A

substrate mimic
transition state mimic

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4
Q

what can be designed to target a receptor

A

natural ligand mimic
monoclonal antibody - stops natural ligand binding or modulating the binding or stopping dimerization in signal transduction

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5
Q

what does a lower Kd indicate

A

a stronger interaction

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6
Q

EC50

A

concentration needed to Elicit 50% of the response

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7
Q

what are good features of possible drug candidate molecules

A

hydrophobic to fit into hydrophobic pocket
a place to form hydrogen bonds for hydrophilic
charge eg. RNH3+, COO- for charged interactions
ring structures, delocalised e- pairs can stack between the pi bonds in Phe or Tyr

these interactions are all weak and non covalent, but the sum of them is strong

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8
Q

IC50

A

concentration of inhibitor to elicit 50% decrease in activity

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9
Q

is IC50 analogous to EC50

A

yes when target is an enzyme or binding partner

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10
Q

selectivity

A

off target binding of drug / target binding to drug

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11
Q

rule of 5

A

poor absorption when
molecular weight >500
no. H bond donors >5
no. of H bond acceptors >10
partition coefficient, log(P) > 5

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12
Q

what features make a molecule a good drug - absorption

A

Lipinski’s rule of 5

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13
Q

what technique can be used to look at the distribution of a drug

A

positron emission tomography (PET) uses 18F so show image of distribution in organs
(only drugs with fluorines)

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14
Q

what is a xenobiotic compound

A

one which is foreign to the host

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15
Q

what are the two stages in the metabolism of xenobiotic compounds process

A

oxidation
conjugation

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16
Q

what is conjugation

A

the addition of a functional group to a xenobiotic molecule so it can be recognised for removal

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17
Q

what are the two pathways of excretion

A

kidneys
enterohepatic cycling

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18
Q

excretion - enterohepatic cycling

A

Compounds that avoid filtration in the kidneys can
be actively transported in to bile and then to the
intestine
further metabolism can occur or drug can be reabsorbed

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19
Q

excretion - kidneys

A
  • Drugs absorbed in kidneys, excreted in urine
  • Blood filtered by glomeruli (capillaries)
  • Compounds less than < 60 kDa pass through
  • Glucose, nucleotides, water etc, some drugs
    reabsorbed,
  • other compounds excreted (urine).
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20
Q

rule of 5 memorising technique

A

5005105
500 - Molecular weight
5 - H bond DONORS
10 - H bond ACCEPTORS
5 - partition coefficient log(P)

21
Q

what is the partition coefficient

A

is given as log(P)
represents the tendency of a molecule to dissolve in membrane
correlates to the ability to dissolve in organic solvents

22
Q

how do you work out therapeutic index

A

LD50/ED50 - lethal dose/effective dose

23
Q

what does Kd equal in terms of receptor + ligand
drug discovery

A

Kd = [R][L]/[RL]

24
Q

example of a compound used for conjugation

A

glutathione

25
Q

what are ways a drug’s “toxic qualities” can limit effectiveness

A
  • Modulate target too effectively
  • Off target effects – same family eg. kinases
  • Off target effects – different family eg. K+ channel hERG
  • Toxic metabolic byproducts
26
Q

why is F a good mimic of H

A

they have a similar van der waals radius
C-H and C-F bonds have a similar bond length

27
Q

what are the effects on the effectiveness of a drug when C-H is substituted for C-F

A
  • Alter lipophilicity – usually an increase
  • Improve metabolic stability
  • Increased bioavailability
28
Q

effects of fluorination on absorption

A

the electronegativity of F means it can shift the pKa or neighbouring amino/carboxylate groups
making them less basic, more lipophilic, distributed better
mean log(P) difference of +0.25 = more lipophilic
however near to O it decreases lipophilicity, possible due to polarisation making the O form stronger H bonds with water

29
Q

what is the effect of fluorination on distribution

A

can modulate binding to human serum albumin - improved bioavailability

30
Q

what is the effect of fluorination on metabolism

A

the C-F bond is stronger than C-H
making oxidation of C-F by cytochrome P450 harder
decreased metabolism = increased bioavailability

31
Q

why might you want to remove fluorines from a drug molecule

A

to reduce a very long half life to an acceptable one

32
Q

L / D chirality

A

relative position of substituents to a reference compound

33
Q

+/- chirality

A

rotation of plane polarized light (enantiomers)

34
Q

R / S chirality

A

absolute configuration around chiral atom

35
Q

screening example

A

aspirin - salicylic acid from willow bark, irritating to stomach
acetylated it - less irritating, more effective

36
Q

structure based design example 1

A

HIV protease inhibitor - substrate mimic
2 parts of the molecule soluble with low activity, one low solubility but with high activity
mortification has increased half life but lowered dose needed
(SARS-CoV2 = example 2)

37
Q

structure based design example 2

A

SARS-CoV2 protease inhibitors - substrate mimic

38
Q

what do protease inhibitors do

A

stops the cleavage of a polypeptide into the different proteins from the different open reading frames (important for viruses)

39
Q

how are protease druggable

A

with a natural substrate mimic - looks like the polypeptide but higher affinity - gets cleaves instead (HIV protease inhibitor) or not - non-hydrolysable peptide analogue (SARS-CoV2 protease inhibitor)

40
Q

what can be included in the medication to extend the half life of protease inhibitors

A

a Cyt P450 inhibitor

41
Q

how is the use of structural data target:inhibitor complexes important

A

it can give you the positions where modification is possible without effecting binding

42
Q

what is the difference between competitive and allosteric modulation of enzymes

A

competitive - orthosteric same site as substrate
allosteric - different site to substrate

43
Q

what is the effect of increasing orthosteric inhibitor concentration on the Michalis menton plot

A

V max stays the same but Km increases (Km = [S] at Vmax/2)

44
Q

what is a good target for an new antibacterial competitive inhibitor and why

A

PDF - peptide deformylase
it deformylates N-formyl methionine (AUG in bacteria)
this is a mechanism not used by eukaryotes

45
Q

what are the 2 ways PDF - peptide deformylase could be targeted

A

orthosterically - something that looks like substrate but not hydrolysable
allosterically - messes with metal ions

46
Q

what does allosteric modulator look like on Michalis menton curves

A

small effect on Km but large reduction of Ki
never reach Vmax that you would have without the inhibitor
- but can also have curves with look like competitive - structural biology needed

47
Q

what is the difference between modulating enzymes vs receptors

A

the output of receptors is not the 1:1 like enzymes - not a linear relationship where fractional occupancy of ES is related to [S]

48
Q

what do antagonists do

A

might alter binding of endogenous agonist
might alter signalling ability of endogenous agonists
might compete for the same site as endogenous agonist

49
Q

example of allosteric modulation drug

A

allosteric inhibitor of isocitrate dehydrogenase 2
overactive enzyme
screening + modification using structural biology
stops substrate pocket from closing up - NADPH too far away for hydride transfer

Biochemistry II (8 decks)

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