| In this paper,firstly,the molecular dynamic simulation experiment and MM-PBSA method were applied to exploring the RMSD,RMSF,protein secondary structure and relative binding freedom energy changing with the simulation time for the E.coli FabB monomer and complexes of FabB with TLM derivatives.Secondly,Fab B inhibitors were screened from ChemDiv library,ADME/T was predicted with FAF-Drugs4 and the binding energy was evaluated using a variety of molecular docking softwares.50 potentially druggative and low-binding energy molecules were screened to summarize the structural characteristics of FabB inhibitor.Finally,based on the antibacterial triazole compounds synthesized by our group previously and FabB and three other antibacterial targets(FabI,FabH and Fts Z),molecular docking was carried out to find out the possible binding targets,put forward its binding mode with the corresponding target and studied the action of triazoles on different targets.Molecular dynamics studies indicated that the FabB monomer was unstable when the inhibitor was absent,the residues of the active site Loop region were also volatile and the secondary structure was unstable.When the inhibitor TLM was present,the carbonyl oxygen at C-2 could form hydrogen bonds with His298 and His333,occupying the active site,and the C-5 isoprenoid side chain could be inserted into the hydrophobic pocket in the Loop region for further immobilization.The introduction of an electron donating group at the C-3 position of TLM facilitated the interaction with amino acids near the active pocket and enhanced the ability to bind to the protein.Introduction of a long-chain group at the C-4 position of TLM hinderd the formation of hydrogen bonds with the key amino acids in the active site,but it could stably occupy the active protein channel.The introduction of the side chain containing the benzene ring at the C-5 position of TLM could form a?-?stacking interaction with Pro272 in the Loop region,which enhanced the fixation of the side chain and introduced a hydrogen bond acceptor such as a carbonyl group,hydrogen bonds could be formed between Gly391 and Gly394 to further fix the side chains.The compounds obtained by the virtual screening have the following characteristics in structure:the inhibitor contains a hydrogen bond acceptor at a portion near the active site and could form one or more hydrogen bond with the triplet Cys163-His298-His333 at the active site of FabB,firmly fixed in the vicinity of the catalytic triad.The rest of the inhibitor could form hydrogen bonding or?-?stacking with the residues on the active site Loop region,stabilizing the protein structure,occupying the active cavity and blocking the entry of the enzyme substrate to achieve the inhibitory effect.The rule of triazole compounds binding to different targets is:the triazole compounds were classified into four groups based on the basic skeleton,in which,the class I,II,III,and IV compounds had better affinity to Fab B and all of them possessd the side chain containing benzene ring which coincide with the isoprenoid side chain of TLM in space,which could form hydrophobic interaction with Loop region of Fab B active site and formed?-?stacking interaction with Pro272;Compounds of class I and III had better affinity to FabI and possessd benzene rings which overlap with the ortho-hydroxyphenyl groups of TCL in space position,which could form?-?stacking interaction with nicotinamide ring of NAD~+and hydrogen bond with key residue Try156 or hydrophobic effect;Compounds of class I and III had good affinity to Fts Z and the binding pattern was similar to that of 9PC,which could interact with Gly205,Val207 and Asn263 and complemented the structure of the active site of FtsZ. |
PDF Full Text Request