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

Abstract Molecular orbital calculations were carried out on a set of 28 non-imidazole H 3 antihistamine compounds using the Hartree–Fock method in order to investigate the possible relationships between electronic structural properties and binding affinity for H 3 receptors (p K i ). It was observed that the frontier effective-for-reaction molecular orbital (FERMO) energies were better correlated with p K i 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 p K i values, the other gathering low p K i value compounds. This separation was obtained with the use of the following descriptors: FERMO energies ( ɛ FERMO ), charges derived from the electrostatic potential on the nitrogen atom (N 1 ), electronic density indexes for FERMO on the N 1 atom ( ∑ ( FERMO ) c i 2 ), 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 Q 2  = 0.88 and R 2  = 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 ) c i 2 , together with low values of electrophilicity and pronounced negative charges on N 1 appear as desirable properties for the conception of new molecules which might have high binding affinity.