Receptor-Ligand Binding Flashcards
agonist
a ligand that binds to and activates the receptor to produce a response in the cell/tissue e.g. acetylcholine
–> binds to and activates the receptor
–> cause conformational change and transduction
–> response (biological effect)
agonist response
direct =
ion channels open/close, transduction mechanisms =
1 enzyme activation/inhibition
2 ion channel modulation
3 DNA transcription
antagonist
a ligand that binds to but does not activate the receptor. it reduces the probability of the agonist binding to receptor thus reduce/block action e.g atropine
binds to and blocks the receptor
–> no conformational change or transduction
–> no response
- will block agonists from binding
ligand -receptor interactions
receptor has recognition site (typically on the outside )
drug targets
- receptors
- ion channels
- enzymes
- transporters
drug actions
drugs cannot create something new but they can modify
* activating e.g. agonist
* enhancing e.g positive modulator
* attentuating e.g positive modulator
* interfering e.g antagonist, no effect itself but lowers response of other agents
different types of receptors
orthosteric vs allosteric
orthosteric vs allosteric
orthosteric = same
–> recognition site of endogenous molecule on receptor e.g agonist and antagonist
allosteric = other
–> other binding on receptor to the orthosteric site e.g modulators bind to allosteric sites
- drugs can still bind to the allosteric site and modify the protein
ligand def
a molecule that binds to the active site on a macro molecule
e.g. agonist and antagonists
allosteric modulators
binds to the allosteric site of the receptor, no effect on its own but can enhance/reduce response to an agonist
–> may alter affinity (strength of binding) or instrinsic efficacy (maximal response you can get ) or both!
Drug Specificity def
For a drug to be useful (therapeutic or scientific) it must act selectively on particular cells or tissues
* Complementary specificity of ligand and binding sites explains many phenomena of pharmacology
–> must have specific shape, charges, complementary bonds, 3d arrangements, size
types of drug specificity
Binding site specificity
* a ligand preferentially binds to one site
- Ligand specificity
- a binding site usually has high specificity for particular ligand(s)
- binding site recognises one type of compound; “ignores” closely related molecules
- change of one amino acid residue on the protein can abolish activity
on target drug side effects
side effects at therapeutic doses by action at the same target in other tissues or regions
morphone binds to u opioid receptors
–> analgesic response (therapeutic effect)
but it can also binds to other opioid receptors in the body = side effects e.g. constipations/vomiting
clozapine at dopamine D2 receptors
* => antipsychotic (therapeutic effect)
* => binds to other dopamine D2 receptors in body
off target drug side effects
Drugs binding to **other targets **at therapeutic doses can lead to side effects
- eg: antipsychotics bind to dopamine D2 receptors but also histamine and muscarinic receptors at therapeutic doses.
- As drug dose increases, opportunity for drug to bind to more targets with lower affinity increases => leads to side effects
- eg: antihistamines at higher doses => start to bind to muscarinic receptors.
complete specificity
No drug acts with complete specificity
* but drugs like atropine (selective muscarinic antagonist) have a high selectivity for muscarinic cholinergic receptors (low affinity for nicotinic cholinergic receptors)
–> need a lot, a very high concentration for atropine to bind to other sites like histamine receptors
- however atropine does not discriminate subtypes of muscarinic receptors (M1, M2, M3, M4, M5)
- No drug acts with complete specificity but can bind selectively
Types of Bonding between drug and target
Most common type : Ionic bonding (cation-anion)
Most common type : Ionic bonding (cation-anion)
* strong attraction between opposite charges
- eg: charged group on drug <=> amino acid side chain at binding site
- potential amino acid residues at receptor
- +ve charge = lysine –NH3+, arginine
- -ve charge = aspartate –CO2- , glutamate –CO2-
–> positively charged residue will attract a negatively charged molecule - strong bonds (~500kJ/mole)
- acts over large distance
Types of Bonding between drug and target
Cation-π interactionsz
Recent appreciation that cation-π interactions are often seen in receptor binding (c.f. cation-anion interactions)
–> binding energies of 25 to 50 kJ/mo
Types of Bonding between drug and target
Covalent bonds
Covalent bonds
o Most drug molecules do NOT use covalent bonds in their mechanism of action (unless they work by inhibiting enzymes)
o Strong bond (~500kJ/mole)
o Difficult to break (irreversible)
o Within a drug molecule, unequal sharing of electrons in a covalent bond can give a large dipole
² eg: phenelzine binding to monoamine oxidase enzyme
Types of Bonding between drug and target
nduced dipole bonds eg: Van der Waals
o Between neutral molecules in close proximity
o Weak per bond (~2kJ/mole), but additive
o Especially important for aromatic groups
and large aliphatic groups
o Can contribute substantial total binding energy
-> eg: amphetamine binding to phenylalanine
residue
Types of Bonding between drug and target
Ion-dipole and Dipole-dipole bonds
Ion-dipole and Dipole-dipole bonds
o More complicated bonding forces
–> dipole = remember, the dipole arises from an unequal distribution of the
electrons. = there’s electron sharing that’s going on here.
–> Weaker than ionic bonds (~150kJ/mole)
o Dependent on correct alignment of bonds, helps orientate molecule (not like large distances like ionic bonds)
- eg: interaction of carbonyl group (-CO) on drug with binding group on receptor
Types of Bonding between drug and target
Hydrogen bonding
Hydrogen bonds
* Act over shorter distances
* Weak bond (~30kJ/mole)
* Very dependent on correct alignment
* eg: drug hydroxyl (-OH) group binding to nitrogen of
histidine imidazole ring
examples of Ionic bonding (cation-anion)
salbutamol = beta two adrenoceptor agonist
–> acts in the lungs to activate the
beta two adrenoceptor
= relaxation of the bronchial smooth muscle
So it has a protonated amino group –> will bind to a dissociated carboxylic acid like we see on aspartate or glutamate.
So negatively charged amino acids attract positvely charged molecules
Summary of Types of Bonding
- Covalent bonds - Most drug molecules do NOT use covalent bonds in their mechanism of action
- Ionic bonds (if present) act first on approach of a molecule to a receptor
- Then dipole and hydrogen bonds to align
- Then induced dipole bonds for final binding
- Note drug binding is usually a reversible process
specificity vs selectivity
High specificity implies fewer off-target effects and side effects because the drug does not interact with other unintended targets in the body.
High selectivity means the drug has a higher affinity for its intended target than for other targets, which can reduce side effects but not eliminate them completely.
- Selectivity = ability of a given drug concentration to produce one effect over another (eg: therapeutic effect over side effect)
Amitriptyline
exmaple : Amitriptyline
It’s an antidepressant = will increase serotonin and noradrenaline concentrations in the brain.
inhibits the reuptake of serotonin and norepinephrine, increasing their levels and activity in the synaptic cleft.
–> binds to and blocks the serotonin and noradrenaline transporters = antagonist
It’s also binding to histamine H1 receptors histamine H2 receptors, a- adrenoreceptors and muscarinic receptors, so it’s having all these other
side effects.
Fluoxetine
therapeutic doses between 10 to the minus eight and 10 to minus nine nM concentrations = binding selectively to the serotonin transporter to inhibit serotonin
reuptake
–> increase the amount of serotonin available in the synapse = improve mood.
When you increase the concentration and dose, start binding to 5- HT2 receptors
Much higher doses for binding at
–> muscarinic receptors, Noradrenaline transporters, dopamine transporters and alpha one adrenoceptors as well.
Drug Targets in the Human Genome
- G Protein-Coupled Receptors
- Ion Channels
- Growth Hormone Receptors
- Nuclear Receptors
- DNA
- Enzymes
Drug Targets : receptors
Receptors
* Ionotropic = ligand-gated ion channels
* Metabotropic = G protein coupled receptors
* Kinase-linked [phosphorylation of downstream signaling molecules]
* Nuclear [ transcription factors = and directly modulate gene expression]
–> receptors use the words agonists and antagonists
Drug Targets : enzymes
inhibitors : binding to and blocking the normal reaction of the enzyme, normal reaction inhibited.
false substrate : binding to and the enzyme’s actually able to catalyse the reaction and produce something = called an abnormal metabolite
–> esembles the substrate of a particular enzyme but is not a valid substrate for that enzyme
pro drug : produce an active metabolite of a drug
–> pharmacologically active compound that produces the desired therapeutic effects in the body.
Drug Targets : transporters
normal transport : Transport ions and molecules into and out of cell
inhibitor : inhibit transport, transport blocked
false substrate : the transporter recognises it and transports it
Drug Targets : ion channels
Ion channels
* Ligand sensitive ICs
* Voltage Gated Ics
–> refereed to as blockers or modulators
blockers : binding to and blocking the ability for the ions to move through the channel.
modulators: bind somewhere else
on the protein, and they will increase/ decrease the ion channel opening probability, dialling it up or dialling it down.
ligand gated ion channels (ionotropic)
gate ion channels permeable to cations and anions
–> ion channels open in miliseconds =FAST
1) the ligand [ACh] binds to a recognition site on receptors [nACh] = the ion channel becomes permeable to cations or anions, [Na+/K+]
hexomethonium : antagonist to the nACh receptors
G protein coupled receptors (metabotropic)
muscarinic acetylcholine (mACh) receptors
takes longer (seconds-minutes) : needs to activate second messenger –> ion channel opening / control of protein phosphorylation
agonists: muscarine, ACh
antagonists: atropine
difference between affinity and potency
affinity is more binding
potency is more the effect it elicits
affinity :
Affinity is often quantified by the dissociation constant (Kd), which represents the concentration of a drug at which half of the receptors are occupied.
A lower Kd indicates higher affinity.
potency:
EC50 represents the concentration of a drug required to produce 50% of the* maximum possible effect*.
A lower EC50 indicates higher potency, meaning that a lower concentration of the drug is needed to achieve the desired effect.
