A quantum chemical study on a set of non-imidazole H3 antihistamine molecules

Molecular orbital calculations were carried out on a set of 28 non-imidazole H3 antihistamine compounds using the Hartree–Fock method in order to investigate the possible relationships between electronic structural properties and binding affinity for H3 receptors (pKi). It was observed that the frontier effective-for-reaction molecular orbital (FERMO) energies were better correlated with pKi values than highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy values. Exploratory data analysis through hierarchical cluster (HCA) and principal component analysis (PCA) showed a separation of the compounds in two sets, one grouping the molecules with high pKi values, the other gathering low pKi value compounds. This separation was obtained with the use of the following descriptors: FERMO energies (ɛFERMO), charges derived from the electrostatic potential on the nitrogen atom (N1), electronic density indexes for FERMO on the N1 atom (∑(FERMO)ci2), and electrophilicity (ω′). These electronic descriptors were used to construct a quantitative structure–activity relationship (QSAR) model through the partial least-squares (PLS) method with three principal components. This model generated Q2 = 0.88 and R2 = 0.927 values obtained from a training set and external validation of 23 and 5 molecules, respectively. After the analysis of the PLS regression equation and the values for the selected electronic descriptors, it is suggested that high values of FERMO energies and of ∑(FERMO)ci2, together with low values of electrophilicity and pronounced negative charges on N1 appear as desirable properties for the conception of new molecules which might have high binding affinity.