receptors are mostly membrane-bound proteins that selectively bind small molecules called ligands...
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Receptor-drug interaction
Receptors are mostly membrane-bound proteins that selectively bind small molecules called ligands which results in physiological response.
They are difficult to isolate because they exist in tiny amount and if isolated it will be difficult to purify.
Receptor-drug interaction
The driving force for drug-receptor interaction is the low energy state of the drug-receptor complex.
The biological activity is related to the drug affinity for the receptor, i.e the stability of the complex.
Dissociation constant of the drug-receptor complex gives an idea a bout how potent is the drug
Interactions involved in drug-receptor interaction
Includes:
Covalent bonding Irreversible bond
Ionic (electrostatic) interaction
Reversible bonds
Dipole-dipole interaction
H-bonding
Hydrophobic interaction
Van der Waals forces
Covalent bonds
Strong, irreversible bonds (-40 to -110 Kcal/mol stability).
Rarely seen in drug-receptor interaction.
More prevalent in drug-enzyme and drug-DNA interaction.
Ionic interaction
This type of bond is weaker than covalent bond (-5 Kcal/mol).
At the same time, it is one of the most prevalent bonds in drug-receptor interaction.
The drug molecule must have opposite charge compared to the ionized amino acids found in the receptor or enzyme. Extent of ionization affects the occurrence of
this bond. The distance between opposite charges has a
role as well.
Ionic-dipole and dipole-dipole interaction
Electronic dipole is formed when we have polarized bond.
In the polarized bond one of the pole will be partially positive and the other partially negative.
These partially positive or negative charges might form an electrostatic bond with either partially charged atoms or ionized elements.
Ionic-dipole and dipole-dipole interaction
O NH
OH
HN
O
XH
O
CH3
ON
CH3
CH3
O N
Hydrophobic pocket
Hydrophobic pocket
HH
CO2
Asn
Asp
Tyr
Practolol inside the adrenergic B-receptorAcetylcholine inside the muscarinic receptor
H-bonding
It can be considered as a subtype from dipole-dipole interaction:
X can be N, O or F Y can be an atom with non-bonded pair of
electrons such as N, O and S.
Stability of this bond is -1 to -7 kcal/mol
X
H
Y
H-bonding
Of two types: Intramolecular H-bonding: which occur within
the same molecule. Intermolecular H-bonding: occurs between two
nearby molecules
OH
O
OH O
H
Intramolecular H-bonding
Intermolecular H-bonding
H-bonding
The occurrence of intramolecular H-bonding could affect the pharmacological action of a drug:
P-hydroxybenzoate has more potent antibacterial action compared to methyl salicylate, it is normally used as food additive as preservative.
OH
O
O
Methyl salicylate
OH
O
O
P-hydroxybenzoate
Charge-Transfer bonds
Occurs between an electron donor group in one molecule and an electron acceptor in another. Electron donors such as alkenes, alkynes and
aromatic ring bearing an electron donating group, and atoms having pairs of non-bonded electrons such as O, N and S
Electron acceptors such as aromatic ring bearing an electron withdrawing group,
These groups might exist in the receptor binding sites: Electron donor a.a such as tyrosine and carboxylates Electron acceptor a.a such as cysteine Having both: such as Histidine, tryptophan and
sparagine
Charge-Transfer bonds
HO
Cl
Cl
CN
Cl
Cl
CN
the antifungal Chlorthalinol bound to tyrosine residue
Van-der Waals forces
Occurs due to temporary non-symmetrical distribution of electron density, this will form temporary dipole that will interact with nearby dipole.
Stability accounts for only -0.5 kcal/mole, this means that this type of bonds are much weaker than other bonds.
Determination of Drug-Receptor interactions
Acetylcholine binding to cholinergic receptor as an example.
Kd : Is the concentration of drug that produce 50% of maximum activity
Log [Ach]
% c
o nt r
act i o
n
Kd
50%
The curve describes muscle contraction in smooth muscle upon administering acetylcholine at different concentration.
There is a direct relationship between the level of contraction and Ach concentration
Maximum response will be obtained after reaching the full saturation of receptors
Unknown drugs will be administered to muscle and study the dose-response curve
Possibilities of unknown’s action
Full agonist: Will give the same maximum contraction as
Ach.
Log [Unknown]
% c
o nt r
act i o
n
Partial agonist/ antagonist: Will give lower level of contraction than Ach.
- Log [Unknown]
% c
o ntr
a ctio
n
Antagonist: Competitive Antagonist
The right shift in response curve means that higher concentration of Acetylcholine is needed (to displace unknown drug from the binding site) to give the same level of activity.
- Log [Ach]
% c
o nt r
a ct io
n
Antagonist: Non-Competitive Antagonist
Muscle contraction is reduced although Ach concentration is increased.
This means that the unknown inhibits the action of Ach after binding to other binding site …. No + effect will be obtained if we will increase Ach concentration
- Log [Ach]
% c
o nt r
a ct io
n
Unkknown in presence of Ach
Agonist vs. Antagonist
Agonist agent: Is compound that will bind to the same
binding site as the natural ligand and similarly activate the receptor.
To do so, It must have close similarity in structure to the natural ligand
HNN
NH2
Histamine
HNN
NH2
H1 agonist
HO
HO
HN
OH
Adrenaline
HO
HO
HN
OH
agonist
Agonist vs. Antagonist Antagonist agent:
Is a compound that strongly bind to the receptor ,inhibits natural ligand from binding, without activating the receptor
Generally it is bulkier than natural ligand, and will form extra bonds….. Different binding pattern
HNN
NH2
Histamine
HO
HO
HN
OH
Adrenaline
NN
N
O
Pyrilamine (H1 antagonist)
NNH
N
NO
HN
HOHN
Timolol (-blocker)