Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design

Hydrogen
bonding is discussed in the context of medicinal chemistry
design. Minimized molecular electrostatic potential (Vmin) is shown to be an effective predictor of hydrogen
bond basicity (pKBHX), and predictive
models are presented for a number of hydrogen bond acceptor types
relevant to medicinal chemistry. The problems posed by the presence
of nonequivalent hydrogen bond acceptor sites in molecular structures
are addressed by using nonlinear regression to fit measured pKBHX to calculated Vmin. Predictions are made for hydrogen bond basicity of fluorine in
situations where relevant experimental measurements are not available.
It is shown how predicted pKBHX can be
used to provide insight into the nature of bioisosterism and to profile
heterocycles. Examples of pKBHX prediction
for molecular structures with multiple, nonequivalent hydrogen bond
acceptors are presented.