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)