Nature of Complex Formation
The binding of a drug to a receptor target represents the sum of multiple intermolecular interactions. A single weak bond is insufficient to ensure secure attachment. 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 the irreversible binding of the drug to the receptor. In pharmacology, this type of interaction is extremely rare.
- Ionic bonds. Arise due to the electrostatic attraction between oppositely charged ions. They are weaker than covalent bonds but stronger than hydrogen bonds.
- Ion-dipole and dipole-dipole bonds. Formed when induced dipoles appear in the electrical field of membranes. Their characteristics are close to ionic bonds and they are very typical for drug-target interactions.
Weak Interactions
Despite the small magnitude of each individual bond, combined they ensure the reliable attachment of the drug to the receptor.
- Hydrogen bonds. Formed 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 occurring between any atoms due to induced polarity (electron shifting). They are only possible at critically short distances — up to 0.2 nm. The slightest separation of the molecules breaks the bond.
- Hydrophobic bonds. Represent the aggregation of nonpolar 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 specific features of the drug's effect.
Reversible Binding This is the primary mechanism for the vast majority of drugs. The complex is held together by weak bonds (hydrogen, van der Waals) and is unstable over time. Periodically, it dissociates into the free drug and receptor, which is described by reversible reaction kinetics.
Irreversible Binding Occurs when a strong covalent bond is formed. In this case, the drug cannot be displaced from the receptor, and its action cannot be rapidly terminated. For the cell to regain sensitivity, it must synthesize new receptor proteins. A prime example is the $\alpha$-blocker phenoxybenzamine, whose effect lasts up to 48 hours (the time required for receptor resynthesis).