Drug Targets (Konorev)

Question 1

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

Answer 1

Receptor

Question 2

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

Answer 2

Inert binding site

Question 3

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

Answer 3

Ligand

Question 4

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

Answer 4

Protein homology domains

Question 5

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

Answer 5

Adaptor proteins

Question 6

Major classes of drug targets:

Answer 6

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

Question 7

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

Answer 7

Signal transduction

Question 8

What are the components of the signaling process?

Answer 8

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

Question 9

What does phosphorylation do in signal transduction?

Answer 9

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

Question 10

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

Answer 10

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

Question 11

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

Answer 11

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)

Question 12

The specific DNA sequence that TFs bind to is called ____

Answer 12

Response element

Question 13

How many targets of pharmacological interest

Answer 13

6000-8000

Question 14

GPCR ligands–biogenic amines

Answer 14

acetylcholine
epinephrine
norepinephrine
dopamine
serotonin
histamine

Question 15

GPCR ligands–peptides/proteins

Answer 15

ACTH
angiotensin
bradykinin
opiods

Question 16

GPCR ligands–amino acids

Answer 16

Glutamate

GABA

Question 17

GPCR ligands–nucleotides

Answer 17

adenosine
ADP
ATP

Question 18

structure of GPCR

Answer 18

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

Question 19

Gs family

Answer 19

activates all isoforms of adenylyl cyclase and Src tyrosine kinase

Question 20

Gi family

Answer 20

inhibits adenylyl cyclase and activates tyrosine kinase src

Question 21

Gq family

Answer 21

activates phospholipase Cbeta

Question 22

heterotrimeric G protein cycle

Answer 22

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

Question 23

cAMP pathway

Answer 23

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

Question 24

IP3 and DAG pathway

Answer 24

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

Question 25

What is GPCR desensitization?

Answer 25

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

Question 26

Mechanism of GPCR desensitization

Answer 26

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

Question 27

Receptors with tyrosine kinase activity transmit action of?

Answer 27

``` IGF-1 VEGF EGF NGF PDGF ```

Question 28

Signal transduction by RTKs

Answer 28

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

Question 29

How do Oncogenses in GF pathways contribute to cancer growth?

Answer 29

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)

Question 30

Ras-->

Answer 30

Raf MEK ERK1/2

Question 31

How do Anticancer drugs inhibit GF signaling?

Answer 31

Antibodies to GF receptors and GF ligands | Multikinase inhibitors

Question 32

Hormones/cytokines that activate the JAK STAT pathway

Answer 32

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

Question 33

Drugs that target JAK STAT pathway

Answer 33

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

Question 34

JAK STAT pathway

Answer 34

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

Question 35

Nuclear receptor ligands

Answer 35

steriod hormones thyroid hormones vitamin D, vit A lipid mediators

Question 36

Steroid receptor family

Answer 36

``` androgen rec estrogen rec progesterone rec glucocorticoid rec mineralocorticoid rec ```

Question 37

Mechanism of steroid hormone action

Answer 37

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

Question 38

ion channels mediates fluxes of

Answer 38

Na, Ca, K, Cl

Question 39

drugs that inhibit voltage gated Na channels

Answer 39

local anesthetics (lidocane) antiarrythmic drugs drugs used for epilepsy

Question 40

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

Answer 40

Used for hypertension, arrythmias, ischemic heart disease

Question 41

Excitatory NTs--examples and what do they do?

Answer 41

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

Question 42

Inhibitory NTs

Answer 42

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

Question 43

Nicotinic acetylcholine receptors causes what?

Answer 43

inward Na fluxes causing membrane depolarization

Question 44

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

Answer 44

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

Question 45

GABA-A receptor causes what?

Answer 45

inward Cl influx and hyperpolarization

Question 46

Drugs that work on GABA-A recepors?

Answer 46

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