Non-covalent interactions
A hydrogen bond (H-bond), is a specific type of interaction that involves dipole-dipole attraction between a partially positive hydrogen atom and a highly electronegative, partially negative oxygen, nitrogen, sulfur, or fluorine atom (not covalently bound to said hydrogen atom). It is not a covalent bond, but instead is classified as a strong non-covalent interaction. It is responsible for why water is a liquid at room temperature and not a gas (given water's low molecular weight). Most commonly, the strength of hydrogen bonds lies between 0 - 4 kcal/mol, but can sometimes be as strong as 40 kcal/mol In solvents such as chloroform or carbontetrachloride one observes e.g. for the interaction between amides additive values of about 5 kJ/mol. According to L. Pauling the strength of a hydrogen bond is essentially determined by the electrostatic charges. Measurements of thousands complexes in chloroform or carbontetrachloride have led to additive free energy increments for all kind of donor-acceptor combinations.
Halogen bond
Aldehyde-based and carboxylate inhibitors are effective but toxic because the functional activity of aldehyde reductase is impaired. Carboxylate and aldehyde inhibitors were shown to hydrogen bond with Trp 111, Tyr 48, and His 110. The “specificity pocket,” created as a result of inhibitor binding, consists of Leu 300, Ala 299, Phe 122, Thr 113, and Trp 111. For inhibitors to be effective, the key residues of interaction were identified to be Thr 113 and Trp 111. IDD 594 was designed such that the halogen would provide selectivity and be potent. Upon binding, this compound induces a conformational change that causes halogen bonding to occur between the oxygen of the Thr and the bromine of the inhibitor. The bond distance was measured to be 2.973(4) Å. It is this O−Br halogen bond that contributes to the large potency of this inhibitor for human aldose reductase rather than aldehyde reductase.