Nature of complex formation
The binding of a drug to a receptor target represents the sum of multiple intermolecular interactions. To ensure secure attachment, a single weak bond is insufficient. A typical complex is held together simultaneously by a dozen Van der Waals interactions and several hydrogen bridges. Meanwhile, strong interactions (ionic and especially covalent) are significantly less common.
Strong chemical bonds
The strongest variants of intermolecular interaction include covalent and ionic bonds.
- Covalent bonds. Formed by a shared pair of electrons. This is the strongest type of bond, leading to irreversible binding of the drug to the receptor. In pharmacology, this type of interaction is extremely rare.
- Ionic bonds. Arise due to electrostatic attraction between opposite charges. In strength, they are inferior to covalent bonds but surpass hydrogen bonds.
- Ion-dipole and dipole-dipole bonds. Formed upon the appearance of induced dipoles in the electric field of membranes. Their characteristics are close to ionic bonds and they are very typical for drug-target interactions.
Weak interactions
Despite the small strength of each individual bond, collectively they ensure reliable attachment of the drug to the receptor.
- Hydrogen bonds. Arise between a positive hydrogen atom and electronegative elements (nitrogen, oxygen, sulfur). A mandatory condition is that the distance between molecules must not exceed 0.3 nm.
- Van der Waals bonds. Universal interactions arising between any atoms due to induced polarity (electron shift). They are possible only at critically small distances—up to 0.2 nm. At the slightest separation of molecules, the bond breaks.
- Hydrophobic bonds. Represent the association of non-polar molecules in an aqueous environment to minimize contact with water.
Reversible and irreversible binding
The nature of the formed bonds directly determines the duration and characteristics of the drug's effect.
Reversible binding Is the main mechanism for the vast majority of drugs. The complex is maintained by weak bonds (hydrogen, Van der Waals) and is unstable over time. Periodically, it dissociates into the free substance and the receptor, which is described by reversible reaction kinetics.
Irreversible binding Arises upon the formation of a strong covalent bond. In this case, the drug cannot be displaced from the receptor, and its action cannot be quickly terminated. For the cell to regain sensitivity, it must synthesize new receptor proteins. A striking example is the $\alpha$-adrenoreceptor blocker phenoxybenzamine, whose effect lasts up to 48 hours (the time required for receptor resynthesis).
Class and exam questions
Which bonds are most characteristic of drug-receptor interactions?
Most commonly, the complex is maintained by a combination of weak bonds: multiple Van der Waals forces, hydrogen bonds, as well as ion-dipole and dipole-dipole interactions.
Why are covalent bonds rare in pharmacology?
Covalent bonds lead to irreversible binding of the drug to the receptor. This makes it impossible to quickly terminate the drug's action, which is often undesirable in clinical practice.
What determines the duration of effect in irreversible binding?
In irreversible binding (e.g., with phenoxybenzamine), the duration of the effect is determined not by the rate of drug elimination from the body, but by the rate of synthesis of new receptors by the cell.
What else to study on this topic
- Reversible reaction kinetics: association and dissociation constants
- Mechanisms of receptor protein resynthesis by the cell
- Specificity of drug binding to alpha-adrenoreceptors
- The role of induced dipoles in the formation of ion-dipole bonds
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