How Drugs Bind to Targets Flashcards by Reem Hamdon

drugs that target intracellular receptors must be… (2)

able to cross pmemb. (lipid-soluble or have a transport mechanism)

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ex of drugs w/ intracellular receptors

steroid hormones

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LBD

ligand-binding domain

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HSP

heat-shock protein

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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

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effects of drugs that bind to intracellular receptors have ____-onset and ____-lasting effects

slow and long (not rapidly reversible)

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GPCRs stands for…

G-protein coupled receptors

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GPCR general cascade

extracellular ligand binding triggers conf. change in receptor which is coupled to intracellular G-protein cascade (separate from receptor)

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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

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G-proteins are (homo/hetero)(di/tri/tetrameric)

heterotrimeric

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which g subunit has GTPase activity?

G alpha

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G beta and gamma subunits can…

influence activity of proteins (stay associated with pmemb.)

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GPCRs are categorized by…

G alpha subtype

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Ga 3 subtypes and targets

Gs: activates adenylyl cyclase
Gi: inhibits adenylyl cyclase
Gq: phospholipase C

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AC stands for…

adenylyl cyclase

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PLC stands for…

phospholipase C

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distinction between Gby and Ga subunit effects

Gby directly affects effector; Ga has affects on initial components that have downstream effects

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G alpha s (AC) cascade (4)

agonist binds to rec, GTP-G(as) activates AC, enzymatic activity converts ATP to cAMP, cAMP activates PKA

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PKA

protein kinase A

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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

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G alpha i general cascade

suppresses AC, cAMP production and PKA activity

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GPCRs vs intracellular (steroid) receptor distinction

GPCRs act very quickly

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G alpha q (PLC) cascade (3)

agonist binds to rec, GTP-G(aq) activates PLC, enzymatic activity hydrolyzes PIP2 to IP3 and DAG

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IP3 cascade (2)

binds to IP3 receptors in ER, Ca is released (can bind to calmodulin)

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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

1. 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.)

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](decr efficacy)

What is B?

Receptor-bound drug