Drug Targets Pharmacology: Receptors, Ion Channels, Enzymes and Carrier Molecules
Types of drug targets
- Every drug when enters the body , it has a target
- Drug targets
- receptors
- ion channels
- enzymes which either intracellular or extracellular
- carrier molecules (transporters)
- Many drugs might bind to plasma proteins or tissue proteins without producing obvious physiological effect
- Some drugs have direct chemical or physical mechanisms or interact with metabolic pathways
- Most drugs work on the receptors
Receptors
- Receptors are protein molecule embedded in the cell membrane, they have an extracellular part and sometimes they have intracellular part.
- When drug bind to a receptor, the drug is called ligand.
- Drugs are also called signals, receptors are signal detectors, and the binding process is called signal transduction.
- When ligand is activating the receptor, it is called agonist, when it inhibit the receptor then it is called antagonist.
- The strength of binding between the receptor and drug is called affinity.
- Occupancy is how many receptors drug occupying on cell, and it increase with increasing affinity
- We have four major receptors types in the human body
- Direct ligand gated ion channel receptors
- G protein coupled receptors
- Tyrosine kinase linked receptor
- Intracellular receptors
Direct ligand gated ion channel receptors
- Direct ligand gated ion channel receptor: 5 transmembrane subunits and have central channel in the middle
- This receptor doesn’t need second messenger
- It is present in tissues needing rapid response like ganglia and skeletal muscle
- This is the fastest receptor type
- These receptors mediate diverse functions including neurotransmission and muscle contraction
G protein coupled receptor
- G protein coupled receptor has extracellular part which contains 7 membrane subunits and it is linked to intracellular part which interact when activated with the G protein which has three subunits, alpha subunit binds guanosine triphosphate (GTP), Beta and gamma subunits anchor the G protein in the cell membrane
- there is different kinds of G proteins Gs, Gi and Gq but they all share the same structure alpha beta gamma
- When agonist bind to the extracellular part , this lead to increase GTP binding to the alpha subunit causing dissociation of the alpha from beta gamma complex and this lead to interaction with effector molecules which produce secondary messengers which interact with specific cellular effectors (usually enzyme or ion channel)
- G stimulatory when activated interact with adenylyl cyclase (effector) which increase C Amp adenosine monophosphate which leads to activation of specific proteins, example is B1 and B2 adrenergic receptors
- G inhibitory also interact with adenylyl cyclase (effector) which decrease C AMP , which lead to inhibition of protein kinases , examples is alpha 2 adrenergic receptors and M2 muscarinic receptors
- the third type of G protein is G q which when activated interact with effector phospholipase C which leads to increase inositol triphosphate (IP3) and Diacylglycerol (DAG) and both of those acts as a second messenger to release the stored calcium in the cytoplasm and lead to action; examples include alpha 1 adrenergic receptors , M1, M3 muscarinic receptors
- G protein coupled receptor is slower than the direct ligand gated receptors, because of the second messenger which takes time
- 70% of receptors in the body are G protein coupled receptors
Tyrosine kinase linked receptors
- it has two large domains, extracellular domain (alpha domain), and intracellular domain (beta domain), and the beta domain linked to tyrosine kinase enzyme, and when activated leads to activation of several proteins known as signaling proteins
- Example: insulin receptors
Intracellular receptors
- Intracellular receptors (Nuclear receptors): they are in direct contact with DNA (entirely intracellular) and when activated changes the expression of genes either increase or decrease.
- Hormones in general work on these receptors like sex hormones (estrogen, progesterone, testosterone), cortisol (steroids )…
- this type of receptor is very slow (takes hours to days to activate) because it has to go through cell membrane and then go to nucleus and work on gene expression which takes time.
- its effect stay for prolonged time.
Drug-Receptor Bonds
- When drug bind to these receptors it makes chemical bonds
- We have 3 main types of bonds
- Ionic bond (electrostatic bond): drug is charged by different charge than receptor, leading to a strong bond because there is transfer of electrons between the drug and receptor
- Hydrogen bonds: attraction between two hydrogen bonds, it is a weak bond
- Covalent bond: there is sharing of electrons between atoms of the drug and receptor, this lead to a strong bond and receptors become permanently occupied with the drug until degradation
Ion Channels
- Drug can work on ion channels by many ways including:
- Drug can block ion channel physically like local anesthetics
- Drug can bind to a receptor that has ion channel in it (direct ligand gated ion channel receptor) and activate the receptor leading to opening of ion channel
- Drug can activate G protein coupled receptor stimulatory type leading to increase C AMP leading to opening of ion channel
- Ion channels maybe modulated by intracellular ATP. E.g ATPase sensitive K+ channels in the pancreatic B cells, rise of intracellular ATP causes closure of pancreatic K channels
Enzymes
- Drug can work on enzymes by many ways including:
- Drug may act as reversible inhibitor of the enzyme, example is neostigmine is a reversible inhibitor of the acetylcholinesterase enzyme
- Drug may act as irreversible inhibitor of the enzyme, example is organophosphates on cholinesterase enzyme
- Drugs works on enzyme as false substrate, L dopa converted by dopa decarboxylase enzyme to dopamine, alpha methyl dopa (drug) act as a false substrate to dopa decarboxylase enzyme but it doesn’t produce dopamine because the methyl group prevent decarboxylation from occurring, so alpha methyl dopa used to compete with L dopa to decrease dopamine level in the body to treat many conditions like hypertension
- Drugs might go to liver and affect CYP450 enzymes leading to induce the activity of these enzymes, or inhibit them
Carrier Molecules
- Those are small protein molecules that carry organic molecules across the cell membrane when they are too large or too polar
- Example: glucose transporters, amino acid transporters, urea transporters
- Drugs can increase carrier molecules or decrease its number, this leads to increase or decrease in transportation