Drug Receptor Interactions

• Drug Targets:

Receptors. • Ligands are compounds that have affinity for a

Enzymes. receptor:

Biomembranes.
Agonist (intrinsic activity).

Nucleic acids.
Antagonist (lacks intrinsic activity).

Ion channels. • Chemical attractive forces.
• Pharmacological action (efficacy).
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• Complementarities assure strong binding:

Three-dimensional characteristics.

Physical and electrochemical properties.
• Strong binding means greater affinity.
• Interaction between the drug and the biologic
receptor would be expected to take place by
utilizing the same bonding forces involved as
those when simple molecules interact.

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 Bond strength
Bond Type Example
(kcal/mol) As organic molecules, drugs bind to their target by:
Covalent 40-140 H3C OH

H 1- Irreversible bonds:
Reinforced ionic 10 R N H O
H O R' o Covalent bonds.
Ionic 5 R4N I o When long lasting effects are desired.
Hydrogen 1-7 OH O o e.g. antibacterials, anticancers.
Ion-dipole 1-7 R4N NR3 2- Reversible bonds:
Dipole-dipole 1-7 O C +
NR3
o Majority of drugs.
o Electrostatic bonds.
van der Waals' 0.5-1 C C
o Hydrophobic bonds.
Hydrophobic 1
o Drugs can easily leave the receptor site.
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Irreversible Bonds: Covalent Bond Covalent Bond: Alkylation

• Ligand and receptor share a pair of electrons.

• Irreversible (50-150 kcal/mole).
• Receptor destruction (suicide binding).
• Aging (Endocytosis and chemical destruction).
• Synthesis of new receptors (recovery).

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Covalent Bond: Phosphorylation Reactivation of Acetylcholinesterase

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Covalent Bond: Acylation Covalent Bond: Metallation

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 Reversible Bonds: Ionic Bond

• Ionizable groups at physiological pH:

Carboxyl.

Sulfonamide.

Aliphatic amino.
• Quaternary ammonium group at any pH.

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Reversible Bonds: Dipole-Dipole or Ion-

Dipole

• Electronegativity.
• Dipoles.
• Electrostatic interactions.
• Dipole-dipole or ion-dipole.
• E.g.: Carbonyl, ester, amide, ether, nitrile, and
related groups.

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Reversible Bonds: H-Bond

• Acceptors and donors.

• E.g.: carbonyl, hydroxyl, amino, and imino.

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• The benzene ring binds flat receptor areas via
van der Waals.
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Reversible Bonds: van der Waals’ Forces
• Non polar compounds.
• Momentary dipolar structure.
• Individually weak.
• Distillation of alkanes (C > 80) requires 80
kcal/mol.
• C–C cleavage requires 80 kcal/mol.
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Reversible Bonds: The Hydrophobic Bond
• Non polar group (e.g. isopropyl).
• Hydrophobic cleft on the receptor.
• Hydrocarbon side chains of the amino acid
valine, isoleucine, and leucine.
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• No H-bonds.
• Not solvated in water.
• Water displacement.
• Van der Waals’ forces.
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Reversible Bonds: Charge Transfer

Complex • Electron-rich donors:

• Electron-rich donor molecules and electron-

deficient acceptors.

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• Electron-deficient acceptors:

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H3C H3C
CH2 O CH3 CH2 O CH3
H3C N CH2 H3C N CH2

H3C H3C
O O
acetylcholine

or

dipole-dipole
or ion-dipole
van der Waals
ion-ion

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