Two Uncharged Atoms Approach Very Closely

Et hac ryn i c Acid

Et hac ryn i c Acid


Keep in mind that it is desirable to have most drug effects reversible. For this to occur, relatively weak forces must be involved in the drug-receptor complex yet be strong enough that other binding sites will not competitively deplete the site of action. Compounds with high structural specificity may orient several weakly binding groups so that the summation of their interactions with specifically oriented complementary groups on the receptor provides total bond strength sufficient for a stable combination. Consequently, most drugs acting by virtue of their structural specificity will bind to the receptor site by hydrogen bonds, ionic bonds, ion-dipole and dipole-dipole interactions, and van der Waals and hydrophobic forces.

Considering the wide variety of functional groups found on a drug molecule and receptor, there will be a variety of secondary bonding forces. Ionization at physiological pH would normally occur with the carboxyl, sulfonamido, and aliphatic amino groups, as well as the quaternary ammonium group at any pH. These sources of potential ionic bonds are frequently found in active drugs. Differences in electronegativity between carbon and other atoms, such as oxygen and nitrogen, lead to an asymmetric distribution of electrons (dipoles) that are also capable of forming weak bonds with regions of high or low electron density, such as ions or other dipoles. Carbonyl, ester, amide, ether, nitrile, and related groups that contain such dipolar functions are frequently found in equivalent locations in structurally specific drugs.

The relative importance of the hydrogen bond in the formation of a drug-receptor complex is difficult to assess. Many drugs possess groups such as carbonyl, hydroxyl, amino, and imino, with the structural capabilities of acting as acceptors or donors in the formation of hydrogen bonds. However, such groups would usually be solvated by water, as would the corresponding groups on a biological receptor. Relatively little net change in free energy would be expected in exchanging a hydrogen bond with a water molecule for one between drug and receptor. However, in a drug-receptor combination, several forces could be involved, including the hydrogen bond, which would contribute to the stability of the interaction. Where multiple hydrogen bonds may be formed, the total effect may be sizable, such as that demonstrated by the stability of the protein a--helix and by the stabilizing influence of hydrogen bonds between specific base pairs in the double-helical structure of DNA.

Van der Waals forces are attractive forces created by the polarizability of molecules and are exerted when any two uncharged atoms approach each other very closely. Their strength is inversely proportional to the seventh power of the distance. Although individually weak, the summation of their forces provides a significant bonding factor in higher-molecular-weight compounds. For example, it is not possible to distill normal alkanes with more than 80 carbon atoms, because the energy of 80 kcal/mol required to separate the molecules is approximately equal to the energy required to break a carbon-carbon covalent bond. Flat structures, such as aromatic rings, permit close approach of atoms. The aromatic ring is frequently found in active drugs, and a reasonable explanation for its requirement for many types of biological activity may be derived from the contributions of this flat surface to van der Waals binding to a correspondingly flat receptor area.

The hydrophobic bond is a concept used to explain attractive interactions between nonpolar regions of the receptor and the drug. Explanations such as the isopropyl moiety of the drug fits into a hydrophobic cleft on the receptor composed of the hydrocarbon side chains of the amino acids valine, isoleucine, and leucine are commonly used to explain why a nonpolar substituent at a particular position on the drug molecule is important for activity. Over the years, the concept of hydrophobic bonds has developed. There has been considerable controversy over whether the bond actually exists. Thermodynamic arguments on the gain in entropy (decrease in ordered state) when hydrophobic groups cause a partial collapse of the ordered water structure on the surface of the receptor have been proposed to validate a hydrophobic bonding model. There are two problems with this concept. First, the term hydrophobic implies repulsion. The term for attraction is hydrophilicity. Second, and perhaps more important, there is no truly water-free region on the receptor. This is true even in the areas populated by the nonpolar amino acid side chains. An alternate approach is to consider only the concept of hydrophilicity and lipophilicity. The predominating water molecules solvate polar moieties, effectively squeezing the nonpolar residues toward each other.

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