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INTERACTIONS
Drug Drug-Receptor
Complex
Ligand-binding
domain k1
Effector domain k2
Receptor
Effect
k1
D+R DR Effect
k2
FORCES INVOLVED IN BINDING OF DRUGS TO RECEPTORS.
• The driving force for the drug-receptor interaction can be considered as a
low energy state of the drug-receptor complex,
• Where kon is the rate constant for formation of the drug-receptor
complex, which depends on the concentration of the drug and the
receptor
• koff is the rate constant for breakdown of the complex, which depends on
the concentration of the drug-receptor complex as well as other forces.
• The biological activity of drug is related to its affinity for the receptor, i.e.,
the stability of the drug-receptor complex.
• This stability is commonly measured by how difficult is for the complex to
dissociate, which is measured by its kd, the dissociation constant for the
drug-receptor complex at equilibrium.
FORCES INVOLVED IN THE DRUG-RECEPTOR COMPLEX
• Covalent bonding
• Ionic interactions
• Ion-dipole and dipole-dipole interactions,
• Hydrogen bonding
• Charge transfer interactions
• Hydrophobic interactions, and
• Van der waals interactions
Development of Drug-receptor theory
1. OCCUPATION THEORY:
2. RATE THEORY
3. THE INDUCED-FIT THEORY OF ENZYME-SUBSTRATE
INTERACTION
4. MACROMOLECULAR PERTURBAION THEORY
5. ACTIVATION-AGGREGATION THEORY / TWO STATE MODEL OF
RECEPTOR ACTIVATION
Other theories
The receptor cooperativity model
The mobile receptor Model
I. Occupation theory (1926)
* Drugs act on independent binding sites and activate them,
resulting in a biological response that is proportional to the amount
of drug-receptor complex formed.
* The response ceases when this complex dissociates.
D + R DR RESPONSE
Efficacy
Potency
Ligand
Affinity: measure of propensity of a drug to
bind receptor; the attractiveness
of drug and receptor
- Receptor inactivation
(protein inhibitors, modifications)
Receptor
Effect
Epinephrine
Cell
Agonist
1.0
Full Agonist
% Maximal Effect
0.6
Partial agonist
0.4
0.2
0.0
0.01 0.10 1.00 10.00 100.00 1000.00
propranolol
epinephrine
Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor
Non-competitive Antagonist: the drug and its antagonist do not compete for the same site
Antagonist
Interact with the receptor
Have affinity but NO efficacy
Block the action of other drugs
Effect only observed in presence of
agonist
Types of Antagonists
Competitive (Surmountable) Noncompetitive- Decrease apparent
decrease apparent Potency maximum efficacy
Competitive Antagonist