Biological receptors are capable of combining with drugs in a number of ways, and the forces that attract the drug to its receptor must be sufficiently strong and long-lasting to permit the initiation of the sequence of events that ends with the biological response. Those forces are chemical bonds, and a number of types of bonds participate in the formation of the initial drug–receptor complex.
The bond formed when two atoms share a pair of electrons is called a covalent bond. It possesses a bond energy of approximately 100 kcal/mole and therefore is strong and stable; that is, it is essentially irreversible at body temperature.
Covalent bonds are responsible for the stability of most organic molecules and can be broken only if sufficient energy is added or if a catalytic agent that can facilitate bond disruption, such as an enzyme, is present. Since bonds of this type are so stable at physiological temperatures, the binding of a drug to a receptor through covalent bond formation would result in the formation of a long-lasting complex.
Although most drug–receptor interactions are readily reversible, some compounds, such as the anticancer nitrogen mustards and other alkylating agents form relatively irreversible complexes.
Covalent bond formation is a desirable feature of an antineoplastic or antibiotic drug, since long-lasting inhibition of cell replication is needed. However, covalent bond formation between environmental pollutants and cellular constituents may result in mutagenesis or carcinogenesis in normal, healthy cells.
The formation of an ionic bond results from the electrostatic attraction that occurs between oppositely charged ions. The strength of this bond is considerably less (5 kcal/mole) than that of the covalent bond and diminishes in proportion to the square of the distance between the ionic species. Most macromolecular receptors have a number of ionizable groups at physiological pH (e.g., carboxyl, hydroxyl, phosphoryl, amino) that are available for interaction with an ionizable drug.
The hydrogen atom, with its strongly electropositive nucleus and single electron, can be bound to one strongly electronegative atom and still accept an electron from another electronegative donor atom, such as nitrogen or oxygen, and thereby form a bridge (hydrogen bond) between these two donor atoms. The formation of several such bonds between two molecules (e.g., drug and receptor) can result in a relatively stable but reversible interaction. Such bonds serve to maintain the tertiary structure of proteins and nucleic acids and are thought to play a significant role in establishing the selectivity and specificity of drug– receptor interactions.
Van der Waals bonds are quite weak (0.5 kcal/mole) and become biologically important only when two atoms are brought into sufficiently close contact. Van der Waals forces play a significant part in determining drug–receptor specificity. Like the hydrogen bonds, several van der Waals bonds may be established between two molecules, especially if the drug molecule and a receptor have complementary three-dimensional conformations and thus fit closely together. The closer the drug comes to the receptor, the stronger the possible binding forces that can be established. Slight differences in three-dimensional shape among a group of agonists and therefore slight differences in fit or strength of bonding forces that can be established between agonists and receptor form the basis for the structure–activity relationships among related agonists.
Figure: Transmembrane signaling mechanism.
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