Study On Molecular Mechanisms Of FabI Inhibitor And Drug Design

In this paper, we first used molecular dynamics simulations, DSSP (Define SecondaryStructure of Proteins) and POVME (Pocket Volume Measurer) to study the conformations ofactive site loop, secondary structure, active site volume and the substrate channel of theFabI-NAD+binary and FabI-NAD+-TCL ternary complex and then elaborate molecularMechanisms of classical inhibitor triclosan. Second, we primary screen compounds from theZINC database by the similarity searches and drug-like filter to build a small moleculedatabase, and then performed structure-based virtual screening, consensus docking andconsensus scoring to identify top twenty compounds binding to FabI. Binding modes of toptwenty compounds with FabI were analyzed to get the potential compounds binding. Third,based on the dynamics simulation studies of the molecular mechanism, the twenty compoundswere sent to conduct the molecular dynamics simulations and were analyzed to determine thestability of interactions between the compounds and FabI, and the molecular mechanism ofcompounds. Finally, according to the scaffold of the potential candidates, o-hydroxyphenyl,Triazole or glycosyl groups were introduced and molecular docking was performed to designnovel FabI inhibitors.The study of the molecular mechanism showed the triclosan restricted the changes ofactive site and the substrate channel. Active site loop formed an ordered, closed and stableconformation and commonly associated with a helical structure in the front of active site.Those made the active site volume change little, the volume distribution concentrated and thesubstrate channel size narrowed or almost closed. In the binary systmes, those are in contrastwith the ternary complex. Triclosan can induce residues of FabI active site, active site loopand hinder the unsaturated acyl chains getting into the catalytic center of FabI through thesubstrate channel, reducing reaction and the elongating cycle of fatty acid synthesis. The twocompouds with known activties exhibited higher bioactivity than triclosan for the S.aureusFabI and the docking conformations were similar to the ligand conformation of crystalcomplex. Twelve indole amide derivatives with similar scaffold and the results of dynamicsimulation showed that those compounds can form interactions with the key residues andNAD+. Three of which were further analyzed in detail and showed that each of them canmake the loop cover the cofactor-binding site, stabilize the key flexible loop region and keepthe substrate channel narrow or closed. Finally, we designed potential FabI inhibitors witho-hydroxyphenyl, Triazole or glycosyl groups with potent affinity to FabI.