Insight into the halogen bonding between PA-1 ligand and pyruvate dehydrogenase complex E1 component by crystal structure, DFT calculation, and molecular docking

Abstract

The binding mode of 5-((4-((4-chlorophenoxy)methyl)-5-iodo-1H-1,2,3-triazol-1-yl)methyl)-2-methylpyrimidin-4-amine (PA-1) was studied using a combination of X-ray crystallography, DFT calculation, and molecular docking approaches. The crystal structure of PA-1 primarily indicated the formation of intermolecular hydrogen bonding and halogen bonding between N-H⋯N and C-I⋯N. DFT calculation demonstrated that the geometric structure of PA-1 is in excellent agreement with the crystal structure. The frontier molecular orbital analysis indicated the important role of the 5-iodo-1,2,3-triazole and benzene ring in the biological activities of PA-1. Further molecular electrostatic potential surface analysis confirmed the possibility of iodine atom participating in the halogen bonding with the negatively charged center; this was validated by the molecular docking study, which showed that the iodine atom of PA-1 could form a halogen bonding with the O atom of Asp521 in the active site of E. coli PDHc-E1. These findings demonstrate that halogen bonding interaction could be used for the further optimization of PA-1 to discover more potent PDHc-E1 inhibitors and antifungal compounds.