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NS2 Pharm > Drug Targets (Konorev) > Flashcards

Drug Targets (Konorev) Flashcards

1
Q

A specific molecule in a biological system that plays a regulatory role. Receptor interacts with a drug and initiates the biochemical events leading to drug effects

A

Receptor

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2
Q

A component of the biologic system to which a drug binds without changing any function

A

Inert binding site

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3
Q

A molecule such as a hormone or a drug that binds to a receptor

A

Ligand

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4
Q

Distinct functional and structural units in a protein that is usually responsible for a particular function or interaction, contributing to the overall role of a protein

A

Protein homology domains

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5
Q

contain a variety of protein-binding domains that link protein partners together and facilitate the creation of larger signaling complexes

A

Adaptor proteins

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6
Q

Major classes of drug targets:

A

Membrane receptors, Nuclear receptors, Ion channels, Transport proteins, Enzymes

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7
Q

Process by which cells transmit, receive and respond to information from their environment and from each other

A

Signal transduction

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8
Q

What are the components of the signaling process?

A
  1. Ligand, a biologically active molecule interacting with receptor–can be endogenous (hormones, NTs) or drugs
  2. Receptor, a protein molecule transmitting the signal to the target cells
  3. Intracellular signaling mechanisms within target cell such as protein kinases and transcription factors
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9
Q

What does phosphorylation do in signal transduction?

A

changes conformation of the protein, its activity, binding to other proteins or localization within the cell
*phosphorylation/dephosphorylation cycle

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10
Q

What do protein kinases do and what are the types of protein kinases?

A

Modify protein by covalently attaching phosphate group to an amino acid residue
Types: Serine-threonine kinases and tyrosine kinases

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11
Q

What is a transcription factor? What is its general mechanism of action?

A

Proteins that bind to specific DNA sequences and thereby control the transcription of genetic information from DNA to RNA; its defining feature is the presence of the DNA binding domain
MOA: They promote (activators) or inhibit (repressors) the recruitment of RNA polymerase to specific genes by binding to enhancer or promoter regions of DNA that are usually adjacent to coding sequence of regulated gene (bind to response element)

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12
Q

The specific DNA sequence that TFs bind to is called ____

A

Response element

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13
Q

How many targets of pharmacological interest

A

6000-8000

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14
Q

GPCR ligands–biogenic amines

A 
acetylcholine
epinephrine
norepinephrine
dopamine
serotonin
histamine
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15
Q

GPCR ligands–peptides/proteins

A

ACTH
angiotensin
bradykinin
opiods

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16
Q

GPCR ligands–amino acids

A

Glutamate

GABA

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17
Q

GPCR ligands–nucleotides

A

adenosine
ADP
ATP

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18
Q

structure of GPCR

A 
7 transmembrane domain formed by polypeptide chain
N terminal (extracellular) domain--often glycosylated
C terminal (cytosolic) domain--contains phosphorylation sites
cytoplasmic loops--contain G protein binding sites
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19
Q

Gs family

A

activates all isoforms of adenylyl cyclase and Src tyrosine kinase

20
Q

Gi family

A

inhibits adenylyl cyclase and activates tyrosine kinase src

21
Q

Gq family

A

activates phospholipase Cbeta

22
Q

heterotrimeric G protein cycle

A

ligand binds GPCR
Receptor activated and releases GDP from G protein
GTP binds
G-GTP regulates activity of effector enzyme or ion channel
signal terminated by hydrolysis of ATP

23
Q

cAMP pathway

A 
ligand binds to hormone rec
Gs activated
Adenylyl cyclase converts ATP-->cAMP
Phospodiesterase hydrolyses cAMP
cAMP dependent kinases
24
Q

IP3 and DAG pathway

A 
ligand binds to hormone rec
G protein
PIP2--PLC-->IP3 and DAG
IP3-->Ca
DAG-->PKC
25
Q

What is GPCR desensitization?

A

reduced cAMP response in continued presence of agonist
If agonist is removed after short time, cells recover full responsiveness to subsequent addition of agonist
if cells exposed to agonist repeatedly or over a more prolonged time period, resensitization fails

26
Q

Mechanism of GPCR desensitization

A

agonist binds to receptor
Rec phosphorylated by GPCR kinase which prevents rec interaction with Gs and promotes binding of B-arrestin
Rec-arrestin complex binds to coated pits which promotes rec internalization
dissociation of agonist from internalized rec reduces beta-arrestin binding affinity–allows dephosphorylation of receptors by a phosphotase–rec returns to plasma membrane
repeated/prolonged exposure of cells to agonist facors internalized recs to lysosomes which promotes rec downregulation

27
Q

Receptors with tyrosine kinase activity transmit action of?

A 
IGF-1
VEGF
EGF
NGF
PDGF
28
Q

Signal transduction by RTKs

A

signal molecule (dimer) binds to RTK
tyrosines phosphorylated
Grb2 (adaptor protein)–SH2 binds to phosphorylated tyrosines; SH3 binds to proline rich sequences
SOS binds to SH3 and gets activated (GTPase)
Ras

29
Q

How do Oncogenses in GF pathways contribute to cancer growth?

A

overexpression/amplification of GFs
point mutations or amplifications of GF recs
Point mutation in Ras (90% of pancreatic adenocarcinomas)
Point mutation in Raf (70% of melanomas)

30
Q

Ras–>

A

Raf
MEK
ERK1/2

31
Q

How do Anticancer drugs inhibit GF signaling?

A

Antibodies to GF receptors and GF ligands

Multikinase inhibitors

32
Q

Hormones/cytokines that activate the JAK STAT pathway

A 
(JAK=cytosolic protein kinase)
GH
erythropoeitin
leptin
interferon
IL2-IL10, IL15
33
Q

Drugs that target JAK STAT pathway

A

recombinant ligands
Rec antagonists
JAK inhibitors approved to use in allergic and autoimmune disorders

34
Q

JAK STAT pathway

A

ligands binds to rec
receptors form dimers
JAK is activated and phosphorylates signal transducers and STAT
STAT dimers go to nucleus and regulate transcription

35
Q

Nuclear receptor ligands

A

steriod hormones
thyroid hormones
vitamin D, vit A
lipid mediators

36
Q

Steroid receptor family

A 
androgen rec
estrogen rec
progesterone rec
glucocorticoid rec
mineralocorticoid rec
37
Q

Mechanism of steroid hormone action

A

nuclear rec bound to hsp90 in absence of hormone–prevents folding into the active conformation of the receptor
binding of hormone ligand (steroid) causes dissociation of the hsp90
stabilizer permits conversion to active configuration

38
Q

ion channels mediates fluxes of

A

Na, Ca, K, Cl

39
Q

drugs that inhibit voltage gated Na channels

A

local anesthetics (lidocane)
antiarrythmic drugs
drugs used for epilepsy

40
Q

drugs that inhibit voltage gated Ca channel– What are they used for?

A

Used for hypertension, arrythmias, ischemic heart disease

41
Q

Excitatory NTs–examples and what do they do?

A

open cation channels–depolarize the cell and induce action potentials
acetylcholine
glutamate

42
Q

Inhibitory NTs

A

open anion channels causing inward anion flux and hyperpolarization preventing action potentials
GABA and glycine

43
Q

Nicotinic acetylcholine receptors causes what?

A

inward Na fluxes causing membrane depolarization

44
Q

Nicotinic acetylcholine receptors are located where? Drugs associated with it?

A

Skeletal muscle–antagonist drugs uses as neuromuscular blockers
Neuronal cells–agonist drugs used for smoking cessation

45
Q

GABA-A receptor causes what?

A

inward Cl influx and hyperpolarization

46
Q

Drugs that work on GABA-A recepors?

A

inhalation general anesthesia drugs
intravenous general anesthesia drugs
ethanol
hypnotic and anti-anxiety benzodiazepine drugs

NS2 Pharm (6 decks)

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