Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design

• Published in: Journal of medicinal chemistry 2016-05, Vol.59 (9), p.4278-4288
• Main Authors: Kenny, Peter W, Montanari, Carlos A, Prokopczyk, Igor M, Ribeiro, Jean F. R, Sartori, Geraldo Rodrigues
• Format: Article
• Language: English
• Subjects: Chemistry, Pharmaceutical; Drug Design; Fluorine - chemistry; Hydrogen Bonding; Hydrogen-Ion Concentration
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01946

Hydrogen bonding is discussed in the context of medicinal chemistry design. Minimized molecular electrostatic potential (V min) is shown to be an effective predictor of hydrogen bond basicity (pK BHX), 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 pK BHX to calculated V min. Predictions are made for hydrogen bond basicity of fluorine in situations where relevant experimental measurements are not available. It is shown how predicted pK BHX can be used to provide insight into the nature of bioisosterism and to profile heterocycles. Examples of pK BHX prediction for molecular structures with multiple, nonequivalent hydrogen bond acceptors are presented.