Molecular docking and dynamic simulation of UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) obtained from Mycobacterium tuberculosis using in silico approach

The UDP-N-acetylenolpyruvoylglucosamine reductase (MurB) catalyzes the final steps of the UDP-N-acetylmuramic acid (UDPMurNAc) formation in the peptidoglycan biosynthesis pathway. The absence of this pathway in mammals made it an attractive target for drug development in Mycobacterium tuberculosis (MTB). In this study, the crystal structure of MurB from MTB (PDB Code: 5JZX and resolution of 2.2 Å) bound to FAD and K + was obtained from Protein Data Bank (PDB). A total of 2157 compounds with the best binding conformations were obtained from the Zinc database through virtual screening. These compounds further screened for drug-likeness, pharmacokinetic properties, physicochemical properties (Lipinski rule of five), and molecular docking analysis to identified ligands with desirable therapeutic properties and good binding energies against MurB. The ligands with the best binding energies were subjected to molecular dynamic (MD) simulation and Molecular Mechanics Generalized-Born Surface Area (MM-GBSA) analyses. The results of the molecular docking and pharmacokinetics analyses revealed that seven compounds (7) had minimum binding energies ranged between – 11.80 and – 10.39 kcal/mol, lower than the binding energy of FAD ( – 10.06 kcal/mol). Four compounds with best binding energies (ZINC19837204 = – 11.80 kcal/mol, ZINC11839554 = – 11.47 kcal/mol, ZINC14976552 = – 10.77 kcal/mol) and ability to interact with the residues (ZINC12242812 = – 10.39 kcal/mol) of the substrate-binding site further selected for the molecular dynamic (MD) simulation analysis. The MD simulation showed that all the four ligands formed stable complexes in the binding site of the MurB after the 50 ns MD simulation. These compounds proposed to be novel inhibitors of MTB after in vivo and in vitro validation.