Drug Targets (Konorev) Flashcards
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
Receptor
A component of the biologic system to which a drug binds without changing any function
Inert binding site
A molecule such as a hormone or a drug that binds to a receptor
Ligand
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
Protein homology domains
contain a variety of protein-binding domains that link protein partners together and facilitate the creation of larger signaling complexes
Adaptor proteins
Major classes of drug targets:
Membrane receptors, Nuclear receptors, Ion channels, Transport proteins, Enzymes
Process by which cells transmit, receive and respond to information from their environment and from each other
Signal transduction
What are the components of the signaling process?
- Ligand, a biologically active molecule interacting with receptor–can be endogenous (hormones, NTs) or drugs
- Receptor, a protein molecule transmitting the signal to the target cells
- Intracellular signaling mechanisms within target cell such as protein kinases and transcription factors
What does phosphorylation do in signal transduction?
changes conformation of the protein, its activity, binding to other proteins or localization within the cell
*phosphorylation/dephosphorylation cycle
What do protein kinases do and what are the types of protein kinases?
Modify protein by covalently attaching phosphate group to an amino acid residue
Types: Serine-threonine kinases and tyrosine kinases
What is a transcription factor? What is its general mechanism of action?
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)
The specific DNA sequence that TFs bind to is called ____
Response element
How many targets of pharmacological interest
6000-8000
GPCR ligands–biogenic amines
acetylcholine epinephrine norepinephrine dopamine serotonin histamine
GPCR ligands–peptides/proteins
ACTH
angiotensin
bradykinin
opiods
GPCR ligands–amino acids
Glutamate
GABA
GPCR ligands–nucleotides
adenosine
ADP
ATP
structure of GPCR
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
Gs family
activates all isoforms of adenylyl cyclase and Src tyrosine kinase
Gi family
inhibits adenylyl cyclase and activates tyrosine kinase src
Gq family
activates phospholipase Cbeta
heterotrimeric G protein cycle
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
cAMP pathway
ligand binds to hormone rec Gs activated Adenylyl cyclase converts ATP-->cAMP Phospodiesterase hydrolyses cAMP cAMP dependent kinases
IP3 and DAG pathway
ligand binds to hormone rec G protein PIP2--PLC-->IP3 and DAG IP3-->Ca DAG-->PKC
What is GPCR desensitization?
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
Mechanism of GPCR desensitization
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
Receptors with tyrosine kinase activity transmit action of?
IGF-1 VEGF EGF NGF PDGF
Signal transduction by RTKs
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
How do Oncogenses in GF pathways contribute to cancer growth?
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)
Ras–>
Raf
MEK
ERK1/2
How do Anticancer drugs inhibit GF signaling?
Antibodies to GF receptors and GF ligands
Multikinase inhibitors
Hormones/cytokines that activate the JAK STAT pathway
(JAK=cytosolic protein kinase) GH erythropoeitin leptin interferon IL2-IL10, IL15
Drugs that target JAK STAT pathway
recombinant ligands
Rec antagonists
JAK inhibitors approved to use in allergic and autoimmune disorders
JAK STAT pathway
ligands binds to rec
receptors form dimers
JAK is activated and phosphorylates signal transducers and STAT
STAT dimers go to nucleus and regulate transcription
Nuclear receptor ligands
steriod hormones
thyroid hormones
vitamin D, vit A
lipid mediators
Steroid receptor family
androgen rec estrogen rec progesterone rec glucocorticoid rec mineralocorticoid rec
Mechanism of steroid hormone action
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
ion channels mediates fluxes of
Na, Ca, K, Cl
drugs that inhibit voltage gated Na channels
local anesthetics (lidocane)
antiarrythmic drugs
drugs used for epilepsy
drugs that inhibit voltage gated Ca channel– What are they used for?
Used for hypertension, arrythmias, ischemic heart disease
Excitatory NTs–examples and what do they do?
open cation channels–depolarize the cell and induce action potentials
acetylcholine
glutamate
Inhibitory NTs
open anion channels causing inward anion flux and hyperpolarization preventing action potentials
GABA and glycine
Nicotinic acetylcholine receptors causes what?
inward Na fluxes causing membrane depolarization
Nicotinic acetylcholine receptors are located where? Drugs associated with it?
Skeletal muscle–antagonist drugs uses as neuromuscular blockers
Neuronal cells–agonist drugs used for smoking cessation
GABA-A receptor causes what?
inward Cl influx and hyperpolarization
Drugs that work on GABA-A recepors?
inhalation general anesthesia drugs
intravenous general anesthesia drugs
ethanol
hypnotic and anti-anxiety benzodiazepine drugs
