drug discovery Flashcards
serendipity example
penicillin beta-lactam inhibits transpeptidase of peptidoglycan synthesis
how can genetic differences modulate drug efficacy
beta blockers on beta-1 adrenergic receptor
different alleles = different effects
AA changes
what can be designed to target an enzyme
substrate mimic
transition state mimic
what can be designed to target a receptor
natural ligand mimic
monoclonal antibody - stops natural ligand binding or modulating the binding or stopping dimerization in signal transduction
what does a lower Kd indicate
a stronger interaction
EC50
concentration needed to Elicit 50% of the response
what are good features of possible drug candidate molecules
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
IC50
concentration of inhibitor to elicit 50% decrease in activity
is IC50 analogous to EC50
yes when target is an enzyme or binding partner
selectivity
off target binding of drug / target binding to drug
rule of 5
poor absorption when
molecular weight >500
no. H bond donors >5
no. of H bond acceptors >10
partition coefficient, log(P) > 5
what features make a molecule a good drug - absorption
Lipinski’s rule of 5
what technique can be used to look at the distribution of a drug
positron emission tomography (PET) uses 18F so show image of distribution in organs
(only drugs with fluorines)
what is a xenobiotic compound
one which is foreign to the host
what are the two stages in the metabolism of xenobiotic compounds process
oxidation
conjugation
what is conjugation
the addition of a functional group to a xenobiotic molecule so it can be recognised for removal
what are the two pathways of excretion
kidneys
enterohepatic cycling
excretion - enterohepatic cycling
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
excretion - kidneys
- 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).
rule of 5 memorising technique
5005105
500 - Molecular weight
5 - H bond DONORS
10 - H bond ACCEPTORS
5 - partition coefficient log(P)
what is the partition coefficient
is given as log(P)
represents the tendency of a molecule to dissolve in membrane
correlates to the ability to dissolve in organic solvents
how do you work out therapeutic index
LD50/ED50 - lethal dose/effective dose
what does Kd equal in terms of receptor + ligand
drug discovery
Kd = [R][L]/[RL]
example of a compound used for conjugation
glutathione
what are ways a drug’s “toxic qualities” can limit effectiveness
- Modulate target too effectively
- Off target effects – same family eg. kinases
- Off target effects – different family eg. K+ channel hERG
- Toxic metabolic byproducts
why is F a good mimic of H
they have a similar van der waals radius
C-H and C-F bonds have a similar bond length
what are the effects on the effectiveness of a drug when C-H is substituted for C-F
- Alter lipophilicity – usually an increase
- Improve metabolic stability
- Increased bioavailability
effects of fluorination on absorption
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
what is the effect of fluorination on distribution
can modulate binding to human serum albumin - improved bioavailability
what is the effect of fluorination on metabolism
the C-F bond is stronger than C-H
making oxidation of C-F by cytochrome P450 harder
decreased metabolism = increased bioavailability
why might you want to remove fluorines from a drug molecule
to reduce a very long half life to an acceptable one
L / D chirality
relative position of substituents to a reference compound
+/- chirality
rotation of plane polarized light (enantiomers)
R / S chirality
absolute configuration around chiral atom
screening example
aspirin - salicylic acid from willow bark, irritating to stomach
acetylated it - less irritating, more effective
structure based design example 1
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)
structure based design example 2
SARS-CoV2 protease inhibitors - substrate mimic
what do protease inhibitors do
stops the cleavage of a polypeptide into the different proteins from the different open reading frames (important for viruses)
how are protease druggable
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)
what can be included in the medication to extend the half life of protease inhibitors
a Cyt P450 inhibitor
how is the use of structural data target:inhibitor complexes important
it can give you the positions where modification is possible without effecting binding
what is the difference between competitive and allosteric modulation of enzymes
competitive - orthosteric same site as substrate
allosteric - different site to substrate
what is the effect of increasing orthosteric inhibitor concentration on the Michalis menton plot
V max stays the same but Km increases (Km = [S] at Vmax/2)
what is a good target for an new antibacterial competitive inhibitor and why
PDF - peptide deformylase
it deformylates N-formyl methionine (AUG in bacteria)
this is a mechanism not used by eukaryotes
what are the 2 ways PDF - peptide deformylase could be targeted
orthosterically - something that looks like substrate but not hydrolysable
allosterically - messes with metal ions
what does allosteric modulator look like on Michalis menton curves
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
what is the difference between modulating enzymes vs receptors
the output of receptors is not the 1:1 like enzymes - not a linear relationship where fractional occupancy of ES is related to [S]
what do antagonists do
might alter binding of endogenous agonist
might alter signalling ability of endogenous agonists
might compete for the same site as endogenous agonist
example of allosteric modulation drug
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
