ligands and drug targets

ligand

a molecule that binds to a target protein, such as a receptor or enzyme, to modulate its function

ion channel

a protein that forms a pore in a cell membrane, allowing the selective passage of ions

kinase

an enzyme that catalyzes the transfer of phosphate groups from high-energy donor molecules to specific substrates in the cell

when are kinases common drug targets?

in diseases involving abnormal cell signaling

G-Protein Coupled Receptor

a type of receptor protein located in the cell membrane that is involved in signal transduction

transcription factor

a protein that regulates gene expression by binding to specific DNA sequences

Kd

a measure of how tightly a ligand binds to its target molecule

what does a lower Kd indicate?

a tighter binding affinity

what are the type of drug receptors?

1. inotropic receptors

2. G-protein coupled receptors

3. tyrosine kinase receptors

4. nuclear receptors

nuclear receptor mechanism

ligand needs to permeate cell membrane and bind to specific target on the nuclei

what is the appearance of tyrosine kinase receptors?

transmembrane receptors consisting of an extracellular binding site and an intracellular tail binding to enzyme

tyrosine mechanism

1. binding of ligand activates the receptor

2. tyrosine amino acid gets phosphorylated

3. relay proteins in cytoplasm get activated

what is the function of the G-alpha stimulate proteins?

increase adenylyl cyclase enzyme which will increase cAMP in the cell

what is the function of G-alpha inhibitory proteins?

decrease adenylyl cyclase which will decrease cAMP in the cell

what is the function of the beta and gamma Gi proteins?

they will activate potassium channels; this will lead to an increase in the potassium outflow and decrease the calcium influx

what is the function of the G-alpha-q proteins?

increase phospholipase C enzyme activity which will convert cell membrane phospholipids to increase protein kinase activity

what is the make up of G-protein receptors?

single polypeptide chain forming several transmembrane domains

what modulates the shape of a G-protein coupled receptor?

binding of a ligand

what type of receptor can be referred to as "lock and key"?

inotropic receptors

ionotropic receptors make up

proteins in the plasma membrane

metabrotropic receptors

involved with metabolic function of the cell

ionotropic receptor mechanism

1. ligand binding to site on receptor leads to conformational change

2. change causes channel to open and influx of ions into cell

3. change in ion concentration triggers cellular response

receptor

site where drug can bind to; cellular macromolecule

what receptor type is comparatively slower in the onset of response?

nuclear receptors

what receptor type is comparatively faster in the onset of response?

ligand-gated ionic channels

what type of receptor has the largest family of drugs?

G-protein coupled receptors

where are receptors located?

1. cell membrane

2. cytosol

3. nucleus

explain the general mechanism of receptors

1. ligand binds to a membrane receptor

2. triggers regulatory signal sent to target cell (intracellular response)

3. physiological or pharmacological response

what are the endogenous ligands?

1. neurotransmitters

2. hormones

what are the exogeneous ligands?

drugs

_______ receptors are molecules on the _.

1. protein

2. cell surface

what are the functions of receptors?

1. ligand binding

2. message propagation or signaling

what are the non-receptors?

1. enzymes

2. carrier transporters

3. ion channels

4. DNA

5. microtubules

what are the reversible chemical forces when looking at the binding of drugs?

1. ionic bond

2. hydrogen bond

3. van der waals

what is an irreversible chemical force when looking at the binding of drugs?

covalent bonds; more common with enzymes

rank the drug binding forces from strongest to weakest

1. covalent

2. ionic

3. hydrogen

4. van der waals

what regulates ionotropic receptors?

agonists

agonist

drugs that mimic endogenous ligands

examples of ionotropic receptors

1. nicotinic acetylcholine receptors

2. GABA-alpha receptor for GABA

3. receptors for glutamate

what kinds of receptors fall under the metabotropic receptors?

• g-protein coupled receptors

• tyrosine kinase linked receptors

how do metabotropic receptors affect metabolic processes in the cell?

activate inner cytoplasmic responses and amplifies cell signal

what process is calcium essential for?

exocytosis

presynaptic neuron

where the neurotransmitter is formed and released after stimulation

synaptic vesicles

where neurotransmitter stored in presynaptic neuron

what is the target of endogenous ligands?

postsynaptic neuron

what are the subtypes of GPCR?

Gs (stimulatory)Gi (inhibitory)Gq

what are the subunits of GPCR?

1. alpha

2. beta

3. gamma

what ion will act inhibitory in ligand-gated ion channels?

chlorine

what ions will act excitory in ligand-gated ion channels?

1. calciums

2. sodium

explain how benzodiazepines (BZDs) are an inhibitory transmitter

they open chloride channels; this means that there will be chloride entering the cell rather than sodium, it will make the charge negative and hyperpolarize the cell

how many subtypes create the GABA-alpha receptor?

5

what is the appearance of the GPCR?

7 alpha helices spanning the plasma membrane

what does it mean if GDP is attached to the G-alpha receptor?

the alpha subunit is inactive

what does it mean if GTP is attached to the G-alpha receptor?

the alpha subunit is activated

what side does the N-terminus of the G-protein face in the cellular membrane?

extracellular side

what side does the C-terminus face in the cell membrane?

towards the cytoplasm

what are the ligands of G-protein receptors?

1. catecholamines

2. seicosanoids

3. lipid signaling molecule

what are the G-protein regulated effectors?

1. adenyl cyclase

2. phospholipase C

3. plasma membrane ion channels selective for calcium and potassium

protein tyrosine kinases mediate the response of…

1. insulin

2. epidermal growth factor (EGF)

3. platelet derivied growth factor (PDGF)

4. cytokines

what is the extracellular portion of tyrosine kinase linked receptors responsible for?

binding the ligand

what is the transmembrane portion of tyrosine kinase linked receptors responsible for?

transmitting the signal through the cell membrane

what is the cytoplasmic portion of tyrosine kinase linked receptors responsible for?

terminates in the cytoplasm

what determines the activation of tyrosine kinase activity?

ligand triggers the phosphorylation of the substrate protein which will then produce the biological response

what are intracellular receptors activated by?

highly lipid soluble hormones

intracellular receptor mechanism

lipid soluble hormone activate receptors and permeate across cell membrane and heads toward nucleus of the cellreceptor drug complex increase binding of RNA polymerasegenes are transcribed

how do the CNS neurotransmitters, glutamate and glycine, elicit their specific effects?

ligand-gated ionic channel response

what are examples of secondary messangers?

1. cAMP

2. calcium ions

3. nitric oxide

4. cGMP

what is the role of the secondary messenger?

helps with activation of protein kinase enzyme through phosphorylation

receptor upregulation

number of receptors attached to cell membrane increases over time

receptor downregulation

number of receptors attached to the cell membrane decreases over time

why does receptor upregulation occur?

• long-term administration of an antagonist leads to a blocking of the normal receptor signaling

• to compensate for this, more receptors will be reproduced to try and restore signaling activity

in receptor upregulation the cells are sensitive to __ or

1. more hormones

2. neurotransmitters

desensitization

refers to a reduced response to an agonist drug due to a long period or high dose

what is the mechanism of desensitization?

loss of receptor function through decreased receptor-coupled signaling components

downregulation

decrease in total receptor number in the cell due to endocytosis internalization which triggers degrading of receptors

what does downregulation do to a cell's sensitivity?

receptors will decrease cell's sensitivity to an agonist or drug

A dog has been administered with a bronchodilator (beta-2 agonist), for asthma. After 6 months of treatment, the animal showed breathing difficulties. What could be the possible cause of this change in the dog's clinical response?

down regulation

efficacy

the drug's ability, once bound, to initiate changes to produce responses

Emax

the maximal response of a drug

potency

the concentration of the drug required to achieve a particular therapeutic effect of a given intensity

drugs with ______ potency usually have a ___ affinity

1. high

2. high

when is the drug more potent?

the lower the dose required to produce a stated response

what does potency depend on?

1. affinity of receptor

2. efficacy of receptor

selective drug

produces only a single effect

what is an example of a selective drug?

heparin as anticoagulant

specific drug

targets one type of receptor or target; can still have multiple effects but overall it is more precise

non-specific drug

binds to multiple receptor types or different targets in the body

what does specificity depend on?

drug-receptor interaction

what is specificity linked to?

macromolecular structure of receptors and 3D structure of binding ligands

what type of drug would morphine be?

non-specific drug