FabF-based Inhibitor Molecular Mechanism And Virtual Screening Of FabB/F Dual Targets

This paper used molecular dynamics simulation,DSSP and MM-PBSA method to research the stability of FabF,FabF-PMN(FabF-Derivatives)system,and the changes of both protein secondary structure and relative free energy.Then,Auto Dock and Vina docking softwares were applied to score the antibacterial database in the Chem Div library consistently.253 compounds with dual target score data of FabF and FabB were selected below-10 k J/mol.The optimal combination mode was also analyzed.Finally,34 dual-target drug compounds were successfully obtained from253 compounds according to ADME / T.The study of the molecular mechanism showed FabF monomer has an RMSD>0.2 nm,which has poor stability.The amino acid residues in the active pocket loop fluctuate greatly,and the secondary structure of protein changed.The binary complex system FabF-PMN(Derivatives)basically reached RMAD stability at the last 10 ns.The inhibitor binds to FabF by forming hydrogen bonds with amino acids such as His303 and His340 in the active pocket,In addition,hydrophobic interactions with the hydrophobic amino acids in the active pocket(Phe202,Phe229,Phe398,etc.)also occur to stabilize the presence of the inhibitor in the active pocket.These studies revealed the mechanism of action of inhibitors on FabF,and provided theoretical basis for the virtual screening,structural optimization and product development of FabF-targeted inhibitors.In the virtual screening,the compounds with good consistency score were mostly long-chain structures,and compounds containing similar structures were classified and analyzed,the results showed that there were sulfonyl,amide,1,2,4 triazole,pyrimidine in the compound.The compounds form hydrogen bonds,π-π stacking and hydrophobicity through donor hydrogen and carbonyl oxygen in the structure and key acid residues in the active pocket,this prevents the acyl substrate from entering the active pocket to complete the catalytic reaction,thus blocking the synthesis of fatty acids to achieve the purpose of antibacterial.Provide a structural basis for the design of new antibacterial agents targeting FabF and FabB.