Comprehensive Search of Target Receptors for Phenothiazines and Phenoxazines as Biological activity using Molecular Operating Environment (MOE)

Abstract

Phenothiazines and phenoxazines show biological activity including antipsychotic activity or carcinogenic activity. However, the target receptors for these compounds are still uncertain. To search for the target receptors, the comprehensive search algorithm (cASE) was introduced into MOE and 11,491 receptors were selected at random from Protein database using Molecular Database Calculator in MOE. Conformational search of fluphenazine was calculated and saved in a database, ultimately contains 74 conformers using MMFF94x force field in MOE. Molecular docking was carried out the most stable conformer and the unstable conformer of fluphenazine using the newly cASE module in MOE. As docking results of 11,491 receptors-two conformers of fluphenazine, the U_dockScores of 1,241,478 obtained by two conformers of fluphenazine into the active site of 10,358 target receptors. Among the docking structures obtained, DAO (PDB code 2E48) might be related to antipsychotic activity. ASEDock performed docking studies of DAO-416 conformers of phenothiazines and phenoxazines. In order to clearly the interaction of the receptors-ligands, the InterFragment Interaction Energy (IFIE) analysis was calculated by Fragment Molecular Orbital method. We discussed on the results of the IFIE analysis, and compared with the docking structure using GOLD.