Section 2.1     A variety of non-covalent interactions can be involved in the recognition of a drug substance by its biological target.

Section 2.2     A binding event between drug and target molecule can be described by the relation ΔG = ΔH–TΔS. Thus, a favorable binding free energy (ΔG) can result from a favorable binding enthalpy (ΔH), increased entropy (ΔS), or both. The nature of the non-covalent interactions involved in drug binding will determine if the process is entropy or enthalpy-driven.

Section 2.3     The strengths of non-covalent interactions are related to the distance between the interacting groups. Some interactions are favorable only over short distances (hydrogen bonds, van der Waals forces) whereas others (ionic interactions) are effective over longer distances.

Section 2.4     The hydrophobic effect is the largest single energetic driving force in most drug binding events. The classical description of the hydrophobic effect is an entropy-driven process that desolvates a hydrophobic surface, releasing water molecules into bulk solution.

Section 2.5     Ionic interactions result from the electrostatic attraction of positively and negatively charged groups. Such interactions are strongest when the interacting groups are not highly solvated, such as in the hydrophobic interior of a protein.

Section 2.6     A hydrogen bond describes the non-covalent interaction between a polarized H–X bond as the “donor” and a Lewis base (most often a lone pair on O or N) as the acceptor. The interaction is ubiquitous in biological macromolecules and in drug binding, where the directional nature of the interaction affords binding specificity and fidelity.

Section 2.7     Sufficiently polarized C–H bonds can also serve as donors of hydrogen bonds. Examples include C–H bonds at the α-carbon of amino acids and those with a neighboring heteroatom (X–C–H, where X = N or O). While generally weaker than N–H or O–H donors, hydrogen bonds based on C–H donors usually pay a smaller desolvation penalty.

Section 2.8     The π face of aryl rings can serve as the Lewis base acceptor of a hydrogen bond from N–H, O–H, and especially C–H donors. These interactions are sometimes called π-hydrogen bonds to distinguish them from more typical hydrogen bonds involving lone pair acceptors.

Section 2.9     Interactions of two aryl rings tend to involve edge-to-face or stacking geometries. Edge-to-face interactions are an example of a π-hydrogen bond and have specific geometric requirements. Aryl-aryl stacking interactions can occur via different geometries and arise from a combination of hydrophobic, van der Waals, and quadrupole interactions.

Section 2.10   Positively charged organic or inorganic cations can form a favorable electrostatic interaction with the π face of aromatic rings. Like other ionic interactions, π-cation interactions can be felt over relatively large distances. These interactions play an important role in the binding of cationic neurotransmitters such as acetylcholine.

Section 2.11   Halogen bonds are non-covalent interactions between a C–X bond donor (X = Cl, Br, I) and a lone pair of electrons on a carbonyl function as acceptor. The geometric requirements of the interaction are similar to those of traditional hydrogen bonds. The interaction of C–F bonds with carbonyl functions, however, is of a different nature, with an orthogonal T-shaped geometry being preferred.

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