Pharmacodynamics : Molecular Binding Flashcards
List the four main protein targets for drug binding.
Receptors
Enzymes
Carrier proteins
Ion channels
There are three types of ion channels . What are they?
Ligand gated ion channels
Voltage gated on channels
Second messenger regulated channels
Example of a ligand gated ion channel
Nicotionic acetylcholine receptor
Examples of voltage gated ions channels
Selective sodium or calcium channels
Enzymes may act in three ways. What are they?
Enzyme substrate
False substrates
Prodrugs
There are two subgroups of enzymes that act as enzyme substrates. What are they?
Reversible and irreversible inhibitors.
Captopril and angiotensin converting enzymes are what type of enzyme substrate ?
Reversible
Two examples of enzyme substrate receptors that are irreversible are?
Aspirin and cyclo-oxygenases
Examples of drugs that act as false substrates are?
Anti cancer drug
What are carrier molecules?
These facilitate the transportation of polar organic molecules and ions across the cell membrane.
Example of a carrier molecule in the body
Carrier proteins that transport ions and organic acids from the renal tubule.
What is a symport channel?
Molecule and ion moving in the same direction
What are antiport channels?
Molecule and in moving in opposite directions
There are four types of receptors in the body
Ligand gated ion channels
G protein coupled receptors
Kinase liked and related receptors
Nuclear receptors.
What is another name for ligand gated ion channels?
Ionotropic receptors
How does dihydropyridine vasodilator drugs work?
Inhibits the opening of the L type calcium channels
How does benzodiazepine tranquillisers work?
By binding a region of the GABA receptor implied to increase the conductance of chloride ions across neuronal membranes during the membrane potential moves the membrane potential faster away from its threshold.
What is the action of sulfonyureas?
Used in the treatment Of diabetes which acts on ATP sensitive potassium channels of pancreatic Beta cells and therefore enhance insulin secretion.
Drugs may target enzymes as ……?
Inhibitors
False substrate
Pro drug
Drugs as enzyme inhibitors
The drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme.
Example of a drug that acts a competive inhibitors of enzymes
Captopril, acts on the angiotensin converting enzymes
Can binding of a drug targeted on enzymes be irreversible. And if so what is an example?
Aspirin acting on cyclo-oxygenase.
Drugs may also act as false substrates
Where the drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway e.g fluorouracil acid replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate, this blocks DNA synthesis and preventing cell division
What are receptors in a pharmacological context?
To a PROTEIN molecule which recognizes and respond to an endogenous chemical signal.
Some drugs can target enzymes and require enzymatic degeneration to convert them from an inactive form to an active form are called
Prodrugs
noradrenaline is a carrier protein that can be inhibited ot have a false substrate . What are they?
Tricyclic antidepressant. …… False substrate 39
Cocaine
Amphetamine And methyldopa are example of false substrates
G coupled proteins as also known as
Metabotropic receptors or. 7-transmembrane spanning receptors.
Kinases linked and related receptors
Large and heterogenous groups of membrane receptors responding mainly to protein mediators.
They have an extracellular ligand binding domain linked to an intracellular domain by a single transmembrane helix. The intracellular domain is usually enzymatic in nature ( protein kinase or guanylyl Cyclase activity.
Kinase linked receptors are used in wha metabolism?
Insulin and various cytokines and growth factors.
Nuclear receptors
Receptors that regulate gene transcription. Located in the cytosol and migrate to the nuclear compartment when a ligament is present
Nuclear receptors are receptors for?
Steroid hormone, thyroid hormone, retinoic acid and vitamin D
Structure of ligand gated ion channels
assembled from four types of subunits: alpha, beta, gamma and delta each of molecular weight 40-58kDA.
Four subunits are hydrophobic.
The pentametric structure possess two alpha subunits and both acetylcholine receptors must be bound before a response is achieved.
The gating mechanism of ligand gated ion channels
Control the fastest synaptic events in the nervous system.
Most excitability neuro transmitters can cause an increase in NA or K+ permeability . E.g nACH
GABA receptors chloride
Causes an inward current carried by ions which eventually leads to depolarization
Describe the oligometric assembly of subunits in ligand gated ion channels?
Subunits surrounded by a pore
How does the G protein receptors get their name?
Due to their association with guanine nucleotides, GTP and GDP
How many subunits does G protein coupled receptors have?
3 subunits : alpha, beta and gamma
Which subunit has the GTPase activity?
Alpha unit,it catalyses the conversion in GTP,to GDP.
What is prenylation?
When all three subunits are anchored together in the membrane through a fatty acid chain
The mechanism of G protein receptors.
In the resting state the alpha and beta gamma subunits of a G protein are associated with other, the GDP bound to the alpha subunit.
When there is a stimulation of the G protein, this causes the cytoplasmic domain to bind to a G protein where by the alpha subunit exchanges a GDP to GTP .
The alpha subunit dissociates from the BY subunits which diffuse to interact within effector proteins .
Examples of effector proteins
Adenylyl Cyclase and phospholipase
mAChRs and adrenoceptors both act in ?
The cardiac muscle
There are five main classes of G alpha subunits
Gas, Gai, GAO, Gaq, G12/13
The deactivation of the effector in G coupled proteins is caused by?
When the bound GTP molecules is hydrolysis to GDP
What are the four main effector targets for G proteins?
Adenylyl Cyclase
Phospholipase C
Ion CHannels
RHo A/ RHO kinase
Wha is the role of Adenylyl Cyclase ?
The enzyme responsible for cAMP formation .
Regulates many aspects of cellular function including , enzymes involved in energy metabolism, cell division, cell differentiation, ion transport, ion channels and the contractile proteins if smooth muscles.
What is the role of phospholipase C?
The enzyme responsible for inositol phosphate and diacylglycerol formation.
What is the role of ion channels as targets in G proteins?
Potassium and calcium channels
What is the role in RhoA/ Rho kinase in the targets of G proteins?
A system that controls pathways responsible for cell growth and proliferation.
G as protein function?
Activates Ca2+ channels and activates adenylyl Cyclase
Gai roles?
.
activates k+ channels and inhibits adenylyl Cyclase
Gao role
Inhibits Ca2t channels
Gaq role?
Activates phospholipase C, when PLC is stimulate it cleaves the membrane phospholipid phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol and inositol-1,4,5- triphosphate (IP3)
G 12/ 13
Diverse ion transporter interactions
What are two of the most common Ga subunits and their functions?
Gas, stimulates adenylyl Cyclase, while Gaq stimulates phospholipase C.
What do kinase linked related receptors respond to?
Protein mediators
What is the role of kinase linked and related receptors? And examples?
Cell division, growth, apoptosis, differentiation, inflammation, tissue repair and immune responses.
Examples include insulin receptors, cytokines and growth factors
What are the main types of kinase linked receptors? Hint RTCSG
Receptor tyrosine kinase (RTK) Tyrosine phosphatase Cytokine receptor Serine/ Threonine kinases Guanylyl cylase
The role of RTK
Includes receptors for hormones and growth factors e.g insulin and epidermal growth factors respectively
Transdue signals by phosphorylation tyrosine residues in the cytoplasmic tail of the receptor.
What is the role of tyrosine phosphatase?
Removes phosphate groups from specific tyrosine residues.
Found in immune cells where they regulate cell activation
What is the role of cytokines receptor?
Lack intrinsic activity but associate with a cytosolic tyrosine kinase when occupied.
Ligand a for this receptor include cytokines and colony stimulating factors involved in immunological responses
What is the role of serine kinases?
Members of the transforming growth family.
Stimulate the growth of normal cells, especially endothelial cells and also growth of cancer cells
Guanylyl Cyclase role in kinase receptors?
Similar to receptor RTK, exert their effects by the production of CGmp.
Facts about nuclear receptors
Seen as ligand activated transcription factors.
Some nuclear receptors can be present in the cytosol and migrate to the nucleus upon activation.
May seen lipid or hormonal signals.
Nuclear receptors are receptors of?
Steroid hormones, thyroid hormones, retinoic acid and vitamin D
Nuclear receptors can be classified into two main classes. What are they?
Class 1: consist of receptors for steroid hormones e.g estrogen and androgen
Class 2: the ligands are generally lipids already present in the cell. E.g. Proliferative activated receptor. Recognizes fatty acids
Liver oxysterol receptor. Acts as a cholesterol sensor in cells.
Class two receptors of nuclear receptors also play a role in?
Endocrine hormone receptors . These include the thyroid hormone receptor, vitamin D, receptor and he the retinoic acid receptor.
