Receptors as drug targets Flashcards
receptors and chemical messengers
crucial to communication systems of body
where are most receptors embedded?
within cell membrane
receptor as natural messenger is known as what type of ligand?
endogenous ligand which binds to site exposed on outer cell surface, causing receptors to change its shape
binds to site exposed on outer cell surface, causing receptors to change its shape,
what fit?
induced fit
The CHANGE in shape triggers further events on membrane and inside cell
NO chemical reactions occurs between messenger and receptor
too many chemical messengers released =
cell “overheat”
too few chemical messengers released
cell become “sluggish”
agonists
drugs that mimic the natural messenger and activate receptor
antagonists
drugs that block receptor - still binds to receptor BUT DOES NOT activate it
natural messenger is blocked from activating it
How to design agonist
1) drug - correct binding groups
2) correctly positioned groups
3) drug must be right size to FIT binding site
what are the important binding groups??
consider:
VDW bonds
Ionic bonds
H-bonds
can different compounds interact in the same way?
similar groups
missing interactions means
POOR activity
binding interactions cannot be TOO strong
neurotransmitter would not be able to leave and receptor cannot return to its original shape
use positions of binding groups to explain difference in ______
activity
enantiomers: mirror imagine, strong?
not strong as strong as original molecule as they are NOT the same shape
not interact with all of the binding region of receptor AT SAME TIME
Pharmacophore
decides if drug will work as messenger or not
(do they contain the correct binding groups with the correct position)
consider size and shape:
with an additional methyl group - Meta-methyl group
STERIC shield; prevents structure from sinking deep enough into binding site for effective binding
level of flexibility in the binding site
how are agonists different in terms of structure to natural messenger?
Binding site: several a.a residues and peptide links - all of which might be capable of interacting with visiting molecule
what are allosteric modulators?
indirect agonist effect.
mimic action of endogenous modulators and enhance action of natural or endogenous chemical messenger
(benzodiazepines used as sleep medicines target allosteric b.s. of the GABAA receptor)
antagonists acting at the binding site
1) drug is right shape to bind to receptor b.s., but FAILS to change the shape of binding site or distorts in wrong way
2) find different binding regions within binding site not used by natural chemical messenger - binding of natural chemical messenger = induced fit (activates receptor)
binding of antagonists leading yo a different induced fit
How to design antagonist? acting OUTSIDE binding site
1) allosteric modulators - ‘modulate’ activity of receptors by either enhancing or diminishing it
2) Umbrella effect - molecule act as shield/ umbrella (antagonist bind yo region of receptor) prevents Normal messenger from reaching b.s.
Partial agonist definition
compound acts as an agonist and produces biological effect,
effect is not as great as FULL agonist
bind in TWO different ways - using different regions in binding site: one binding activates the receptor(agonist effect) / others not does (antag effect)
conformational change induced
not ideal and subsequent effects of receptor activation are decreased
what is a receptor subtype?
defined by the pharmacological characteristics of the site and is based on the availability of selective agonists and antagonists for the subtypes
What is the receptor theory? see graph on PP
receptors does not have fixed inactive conformation
continue to change shape
equilibrium A) resting state <> agonist binding site
B) addition of agonist <> b.s. taken
C) addition of antagonist <> blocking
D) addition of INVERSE agonist <>
e) addition of partial agonist
equilibrium is shifted to active conformation but not to full extent as a FULL agonist (e - partial)
affinity
of drug for receptor is a measure of how strongly that drug bind to receptor. aff constant (Ki)
efficacy
measure of the max biological effect that drug can produce as a result of receptor binding
does comp w high aff have high eff
not necessarily
potency
refers to amount of drug require to achieve a defined biological effect - smaller the dose required = more potent
possible for drug to be potent (i.e. active in small doses) low efficacy
how is aff, eff and potency measured?
dose-response curves; eff refers to max effect potency to dose req to achieve and effect
potency is measure by ___% effective conc, EC_
(similary to IC_ in enzyme inb=inhibition); units of conc
50%
50
50
