COX-Ligand Docking study of alkyl-and aryl pyrazines as platelet aggregation inhibitors using Molecular Operating Environment(MOE)

Abstract

We reported that simple alkyl- and arylpyrazines were showed the 50% inhibitory concentration towards arachidonic acid-induced and collagen-induced aggregation of rabbit blood platelet in vitro. Among the 48 pyrazine derivatives, 2,3-bis(p-methoxyphenyl)pyrazines showed the most potent inhibitory activity. Therefore, molecular docking was carried out using the ASEDock module in the MOE. As results of the ASEDock, among the three interaction energies, the van der Waals interaction energies were contributed to the stability of receptor-ligand complexes. The Docking structures suggested the interaction between phenyl groups at 2,3 position and TYR385 and PHE518 and between the substituents at 5,6-position and ARG120. In order to clearly the interaction of the COX-ligands, the InterFragment Interaction Energy (IFIE) analtsis was calculated by Fragment Molecular Orbital method. Consequently, the most strongly interaction energy of the ARG120-ligand calculated to be -17.1 kcal/mol. Thus, the substituents at 5,6 position of pyrazine ring suggests that these sybstituents would enhance the activity, this can be correlated with the presence of ARG120 that can from a salt bridge type of strong electrostatic interaction or the Pi electron-cation stacking with ARG120.