How Drugs Bind to Targets Flashcards
drugs that target intracellular receptors must be… (2)
able to cross pmemb. (lipid-soluble or have a transport mechanism)
ex of drugs w/ intracellular receptors
steroid hormones
LBD
ligand-binding domain
HSP
heat-shock protein
4 steps for drugs binding to intracellular receptor
- drug binds to LBD
- HSP or other chaperone is displaced
- drug/receptor complex translocates to nucleus and binds to response element
- DNA recognition domain is exposed, target genes are transcribed
effects of drugs that bind to intracellular receptors have ____-onset and ____-lasting effects
slow and long (not rapidly reversible)
GPCRs stands for…
G-protein coupled receptors
GPCR general cascade
extracellular ligand binding triggers conf. change in receptor which is coupled to intracellular G-protein cascade (separate from receptor)
GTP activity of G-protein (4)
receptor activation promotes GDP to GTP exchange of G-protein, Ga and Gby subunits dissociate, GTP hydrolysis by Ga acts as timer for signal termination, G-proteins reassemble
G-proteins are (homo/hetero)(di/tri/tetrameric)
heterotrimeric
which g subunit has GTPase activity?
G alpha
G beta and gamma subunits can…
influence activity of proteins (stay associated with pmemb.)
GPCRs are categorized by…
G alpha subtype
Ga 3 subtypes and targets
- Gs: activates adenylyl cyclase
- Gi: inhibits adenylyl cyclase
- Gq: phospholipase C
AC stands for…
adenylyl cyclase
PLC stands for…
phospholipase C
distinction between Gby and Ga subunit effects
Gby directly affects effector; Ga has affects on initial components that have downstream effects
G alpha s (AC) cascade (4)
agonist binds to rec, GTP-G(as) activates AC, enzymatic activity converts ATP to cAMP, cAMP activates PKA
PKA
protein kinase A
cAMP binding to PKA cascade (3)
cAMP binds to 2 R (reg) subunits of PKA, 2 C (cat) subunits dissociate, cat subunits phosphorylate substrates w/ ATP
G alpha i general cascade
suppresses AC, cAMP production and PKA activity
GPCRs vs intracellular (steroid) receptor distinction
GPCRs act very quickly
G alpha q (PLC) cascade (3)
agonist binds to rec, GTP-G(aq) activates PLC, enzymatic activity hydrolyzes PIP2 to IP3 and DAG
IP3 cascade (2)
binds to IP3 receptors in ER, Ca is released (can bind to calmodulin)
DAG cascade (2)
activates PKC which phosphorylates substrate w/ ATP
PKC stands for…
protein kinase C
TKRs stands for…
tyrosine kinase receptors
TKRs general cascade (4)
extracellular ligand binds to TKR causing dimerization, activation by autophosphorylation, phosphorylation of substrates w/ ATP
TKR ligand ex
EGF
TKRs vs GPCRs distinction
TKR is a receptor and a kinase that has effects on substrates (smaller cascade vs GPCRs)
Intracellular receptors (IR) vs cell surface receptors (CSR): memb. permeable drugs?
IR: yes
CSR: not necessary
distinction between steroid hormone receptors vs GPCRs and TKRs
GPCRs and TKRs are cell surface receptors whereas steroid hormone receptors are intracellular
Intracellular receptors (IR) vs cell surface receptors (CSR): circulating form of drug?
IR: bound to carrier globulin bcse low solubility in plasm (aq)
CSR: variable
Intracellular receptors (IR) vs cell surface receptors (CSR): speed of response?
IR: slow (DNA binding)
CSR: fast (conf. change)
Intracellular receptors (IR) vs cell surface receptors (CSR): response termination speed?
IR: slow (hydrophobic hormone usually bound to protein and gene expression is slow to reverse)
CSR: fast (rapid GTPase cycle)
what is the fastest mechanism of signalling?
ion channels/elec. signalling (change in Vmemb.)
2 types of ion channels
- ligand-gated
2. voltage-gated
voltage-gated ion channel response of charged aa
change in V causes charged aa to move into transmembrane area
agonism
substance/drug binds to a receptor and influences its activity
curve that depicts drug activity
concentration-response curve
EC50 stands for…
effective concentration 50
EC50 is the…
[drug] to yield 50% max. effect
Emax
max. biological effect of a drug
E equation
E = Emax. / 1 + (EC50 / [drug]) OR E = (Emax. x [drug]) / ([drug] + EC50)
efficacy and relationship w/ Emax.
max. drug response; linear relationship w/ Emax.
potency and relationship w/ EC50
concentration dependence; inverse relationship w/ EC50
agonists are usually categorized based on their…
efficacy (size of response, height of graph)
antagonist bind to receptor and generate…
no response on their own
inverse agonists bind to receptor and…
suppress basal activity, if present (can be negative)
full agonists bind to receptor and generate…
maximal response (Emax.)
partial agonists bind to receptor and generate…
a fractional response (partial Emax.)
antagonism
substance/drugs that binds to a receptor and influences its response to an agonist
competitive antagonist
a compound that occupies the same binding site as agonist but does not elicit a response
non-competitive antagonist effect of potency/efficacy
reduce agonists efficacy but not potency (decr Emax., same EC50)
competitive antagonist effect on potency/efficacy
requires a higher conc. of agonist to generate a given response, potency but not efficacy is altered (same Emax., incr EC50)
surmountable antagonist
high enough conc. of agonist displaces antagonist to achieve same Emax.
Schild plot
measures dose ratio vs conc. of antagonist
dose/conc. ratio
ratio of agonist EC50 w/ and wo/ an antagonist
dose ratio equation
EC50 w/ antagonist / EC50 control
x-intercept (pA2/pKi) of Schild plots reflect…
antagonist potency (small [antagonist] to double EC50 of agonist = strongly potent antagonist)
how are Schild plots linear?
use log scales
popular competitive antagonist for opioid receptors ex
naloxone
t/f: partial agonists cannot act as antagonists
false, compete w/ agonist and decr response
irreversible competitive antagonism
antagonist binds irreversibly to drug binding site and are not surmountable by agonist (might be referred to as noncompetitive antagonism)
pure noncompetitive antagonism is…
binding of antagonist to allosteric site preventing activation of agonist bound receptor
t/f: noncompetitive antagonists are surmountable
false
allosteric potentiators
drugs/compounds that bind to an allosteric site and enhance agonist effect to receptor binding
allosteric potentiators effect
incr efficacy, potency or both of agonist
action of benzodiazepines
allosteric potentiators for GABA receptors (ligand-gated Cl channels) to alleviate symptoms of hyperexcitability from alcohol withdrawal
allosteric potentiators effect on concentration-response curve
shift to left (same [GABA] = incr response)
do [drug] vs drug bound and drug effect have the same relationship? why?
not always; amplification of response (more receptors present than needed for Emax.)
Kd
dissociation constant; [drug] where 50% is bound to receptors
B equation
B = (Bmax x [drug]) / ([drug] + Kd)
ex of distinction btwn [drug] needed for Emax. vs all receptors bound
activation of a single GPCRs can generate many cAMP molecules and activate many PKAs (amplification)
receptor reserve phenomenon
adding small amounts of irreversible competitive/noncompetitive antagonist still generates Emax. with incr [agonist] due to excess receptors (decr EC50/potency) until [antagonist] overcomes min. number of receptors needed to achieve Emax. w/ incr agonist
What is B?
Receptor-bound drug
