Structure-based rational design of novel hit compounds for pyruvate dehydrogenase multienzyme complex E1 components from Escherichia coli

Pyruvate dehydrogenase multienzyme complex (PDHc) E1 component plays a pivotal role in cellular metabolism to convert the product of glycolysis (pyruvate) to acetyl-CoA, and has been reported as a potential target for anti-microbial and herbicide. In present study, based on the thiamin diphosphate (ThDP) site, four novel hit compounds with high inhibitory activity against the PDHc-E1 from Escherichia coli were firstly designed by using structure-based molecular docking methods. As expected, among four compounds, the compound 3a is the best inhibitor by far, with IC₅₀ value of 6.88 μM against PDHc-E1 from E. coli. To elucidate the interaction mechanism between the active site of PDHc-E1 and its inhibitor, the docking-based molecular dynamics simulation (MD) and MD-based ab initio fragment molecular orbital (FMO) calculations were also further performed. The positive results indicated that all modeling strategies presented in the current study most like to be an encouraging way in design of novel lead compounds with structural diversity for PDHc-E1 in the future.