Development of pharmacophore model based on multiple FMO analysis

Abstract

In order to obtain novel compound for drug discovery, it is important that predicting pharmacophore which is common or specific characteristics among active compounds. When target protein-ligand complex structure is available, molecular mechanics method is often used to analyze the interaction between target protein and ligand. However, that method is not applicable to all ligand because there is a limit to the determination of molecular potentials based on atom type, especially of quantum chemical elements such as π electrons. In this study, we focused on dihydroorotate dehydrogenase (DHODH) of Trypanosoma cruzi, a target protein of Chagas disease. We identified pharmacophores using the Fragment Molecular Orbital (FMO) method, which employs ab initio quantum mechanical calculations. We analyzed interaction energy between TcDHODH and orotate, oxonate as a competitive inhibitor of TcDHODH, and 43 orotate derivatives. As a result, 4 common pharmacophore and 1 specific pharmacophore were obtained. Furthermore, compounds that met the specific pharmacophore was suggested to bind to TcDHODH selectively, rather than Human DHODH.