Study On Molecular Mechanisms Of ?-ketoacyl-ACP Reductase (FabG) Inhibitor And Drug Design

?-ketoacyl-ACP reductase(FabG)is the second enzyme in the extended cycle of the bacterial fatty acid synthesis pathway and catalyzes NADPH-dependent reduction of?-ketoacyl-ACP intermediates.FabG is a member of the short-chain dehydrogenase/reductase(SDR)protein superfamily.Epigallocatechin gallate(EGCG)is the major component of green tea extracts.EGCG is a potent inhibitor of the?-ketoacyl-ACP reductase(FabG)components in the bacterial type II fatty-acid synthase system,a property that is common to a broad range of plant polyphenols.In this paper,we investigated the mechanism of action of EGCG and related plant polyphenols on?-ketoacyl-ACP-reductase(FabG).Firstly,we used molecular docking,MD simulation,DSSP,and MM-PSBA methods,to calculate such parameters of various interactions between EGCG and related plant polyphenol ligands with FabG complex systems as RMSD,Rg,RMSF,hydrogen bonds,secondary structure,and relative combined with free energy.Then we studied the changes and laws of change of these parameters as a function of molecular dynamics simulation.Experimental results shows that when no ligand is present,the FabG monomer system has poor stability,a small radius of gyration,and a relatively compact protein folding and the amino acid residues in the flexible region near the active channel fluctuate greatly,and the secondary structure is unstable.When EGCG or related plant polyphenols was present,the side chain hydroxyl groups may form hydrogen bonds with the key residues Ser138,Tyr151 of the active site or with the key residues Asp92,Gln148,and Ile184 of the Loop region,occupying the active site.At the same time,the ligand can also form hydrogen bonds and?-?stacking interaction with the coenzyme NADPH to further immobilize the side chain.Secondly,the antibiotic bioactive triazole compound containing o-hydroxyphenyl group synthesized in the previous stage of the research group was constructed into a small molecule compound library.Molecular docking screening was then performed with FabG and three other antimicrobial active targets(FabI,FabH,FabB).Explore the binding mode of these compounds to various targets and study the interaction between ligands and different targets.The results of the study indicate that triazole compounds containing o-hydroxyphenyl groups are classified into four classes by chemical structure.Among them,these four compounds show good affinity to both FabG and FabB.The compounds of Groups I and III form a hydrogen bond or a?-?stack with the nicotinamide ring of the coenzyme NAD~+of FabI,and exhibit strong binding ability.