Drug Design And Antibacterial Activities Base On The Bacterial Cell Leli Division Protein FtsZ

In this paper, the complex stability, secondary structure, protein conformation, residue distance, active site volume, and binding free energy of the Sa Fts Z(filamentous sensitivity division protein Z of Staphylococcus aureus)-GDP(Guanosine diphosphate) binary complex and the 3MBA derivatives ternary complex were studied by molecular dynamics simulations mechanics-Poisson-Boltzmann surface area(MM-PBSA). Then a series of compounds which acted on Fts Z was designed by Lig Builder v2.0. And eighteen compounds with potential drug ability and lower docking energy were obtained by ADME/T(absorption, distribution,metabolism, excretion and toxicity) prediction and molecular docking. Construct Sa Fts Z-GDP-inhibitor ternary complex by selecting typical ligands(02-49, 09-32, 146-75 and the reported inhibitor 9PC). The 10 ns molecular dynamics simulations was performed. At last based on Sa Fts Z protein T7 Loop active pocket, we have established a virtual screening work flow using molecular docking and ADMET properties. twenty-five molecules were bought out of about fifty compounds from the Specs database and were evaluated for their antimicrobial activities.Molecular dynamics simulations indicate that: the Sa Fts Z-GDP binary complex in the absence of inhibitor was unsteady and the residues of its T7 Loop area fluctuate obviously, at the same time, the secondary structure of protein in T7 Loop area changes remarkably, the active pocket volume decreases sharply and the substrate channel size also becomes narrow and unstable. But the Sa Fts Z-GDP-3MBA derivatives ternary complex in the presence of the inhibitor PC190723 or Compound1 appears in a completely different way. Both of them can form hydrogen bondings and hydrophobic effects with high affinity on Fts Z, so that system is stability. But the Sa Fts Z-GDP-3MBA derivatives ternary complex in the presence of the inhibitor PC190723 or Compound1 appears in a completely different way. Both of them can form hydrogen bondings and hydrophobic effects with high affinity on Fts Z.However, for the Sa Fts Z-GDP-3MBA ternary complex, the ligand only forms hydrophobic effects with partial residues of the active pocket as a function of simulation time, with the result that 3MBA could not stably exist in the active pocket for low affinity. So antibacterial activity of 3MBA is significantly lower than that of PC190723 or Compound 1.The findings on the novel drug design show that 18 small molecules which has the potential of medicines and lower binding energies was potential Fts Z inhibitors. Hydrogen bonds and Hydrophobic interactions are generated between these copounds and residuesaround the active pockets. The results of virtual screening based on the NCCLS indicate that all of the testd compounds show a promising antibacterial activity against Staphylococcus aureus with MIC values ranging from 1 to 64 μg·m L-1, against Monilia albican with MIC values ranging from 4 to 64 μg·m L-1, against Escherichia coli with MIC values ranging from4 to 256 μg·m L-1, and a poor antibacterial activity against Bacillus subtilis with MIC values ranging from 16 to 256 μg·m L-1. Especially, compounds 1 and 20 show excellent antibacterial activities against Staphylococcus aureus with the same MIC value of 1 μg·m L-1. The docking studies provided a valuable information to design novel Fts Z inhibitors.