Theoretical Calculation of Hydrogen-Bonding Strength for Drug Molecules.

Hydrogen bond is an important type of interaction between drug molecules and their receptors. We present here a computational method for accurately predicting the hydrogen-bonding strength for different acceptors with respect to a given donor or vice versa. The method is based on quantum chemistry DFT calculation of the interaction energy between hydrogen bond donors and acceptors. An excellent linear correlation is observed between the calculated hydrogen-bonding energies and the experimentally measured hydrogen-bonding constants log Kβ on a variety of known hydrogen bond acceptors and donors. These results not only indicate the predictive power of this method but also shed light on factors that determine the magnitude of experimentally measured hydrogen-bonding constants for different acceptors with respect to a given donor, suggesting a primarily enthalpic contribution from hydrogen-bonding energy. The method can be used for evaluating the effects of steric interference and inhibitor binding geometry on hydrogen-bonding strength in drug design.