Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design

Abstract

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.

Synthesis and Biological Evaluation of New Triazolo‐ and Imidazolopyridine RORγt Inverse Agonists

“…The two isomers have similar shape but different electronic distribution. The nitrogen atoms in the oxadiazoles are strong hydrogen bond acceptors, whereas the oxygen atoms are much weaker . In compound 33 the nitrogen adjacent to the oxygen is believed to overlap with the carbonyl group of 10 , thus better mimicking the key C=O⋅⋅⋅H479 hydrogen bond interaction.…”

“…The nitrogen atoms in the oxadiazoles are strong hydrogen bond acceptors, whereas the oxygen atoms are much weaker. [14] In compound 33 the nitrogen adjacent to the oxygen is believed to overlap with the carbonyl group of 10,t hus better mimicking the key C=O···H479h ydrogen bond interaction. The extra nitrogen ortho to the tert-butyl group is not needed for affinity (i.e., compare 33 with 37).…”

Toward a uniform description of hydrogen bonds and halogen bonds: correlations of interaction energies with various geometric, electronic and topological parameters

“…27 In view of the importance of hydrogen bonds, it is of great interest to study the relationships between different measures of the strength of hydrogen bonds, and this topic has been presented in many recent publications. [28][29][30][31][32][33][34][35][36][37][38][39] These relationships fall mainly into two categories. One is the connection between experimentally determined hydrogen bond strengths and theoretically derived quantities.…”

Gaussian Process Regression Models for the Prediction of Hydrogen Bond Acceptor Strengths

“…derived a model with an accuracy of approximately 2 kJ mol −1 by computed COSMO polarization charge densities of HBA atoms. Popelier, Kenny and Besseau applied the minimum of the electrostatic potential ( V min ) and QC topology descriptors as effective descriptors for p K BHX values. Very recently, geometric HB features were proposed for the prediction of HBA strengths …”