Electronic structure and PCA analysis of covalent and non-covalent acetylcholinesterase inhibitors

Hartree-Fock and density functional methods were used to analyze electronic and structural properties of known drugs to evaluate the influence of these data on acetylcholinesterase inhibition. The energies of the frontier orbitals and the distances between the more acidic hydrogen species were investigated to determine their contributions to the activity of a group of acetylcholinesterase inhibitors. Electrostatic potential maps indicated suitable sites for drugs-enzyme interactions. In this study, the structural, electronic and spatial properties of nine drugs with known inhibitory effects on acetylcholinesterase were examined. The data were obtained based on calculations at the B3LYP/6-31 + G(d,p) level. Multivariate principal components analysis was applied to 18 parameters to determine the pharmacophoric profile of acetylcholinesterase inhibitors. Desirable features for acetylcholinesterase inhibitor molecules include aromatic systems or groups that simulate the surface electrostatic potential of aromatic systems and the presence of a sufficient number of hydrogen acceptors and few hydrogen donors. PCA showed that electronic properties, including the HOMO-1 orbital energy, logP and aromatic system quantity, as well as structural data, such as volume, size and H-H distance, are the most significant properties.