Blocking the catalytic mechanism of MurC ligase enzyme from Acinetobacter baumannii: An in Silico guided study towards the discovery of natural antibiotics

Abstract

Acinetobacter baumannii belongs to the most critical group of bacterial pathogens that are resistant to large number of antibiotics, including the highly effective carbapenems and third generation cephalosporins. Novel antibiotics targeting unique pathways of the said pathogen could reduce the mortality rate due to its infections that are impervious to the current antibiotics. Herein, we explored a library of natural compounds that was filtered first for drug-like, followed by lead-like molecules, which were finally utilized in structure based virtual screening to identify the most promising inhibitor for the Ligand binding (LB) domain of MurC ligase enzyme. The inhibitor (1′-((2H-imidazol-2-yl)methyl)-N-(pyridin-2-yl)-1′,2′-dihydro-[4,4′-bipyridin]-2-amine) was observed with a conformation to target most conserved and catalytically critical residues of both the intended LB as well as the ATP binding domain of MurC. This multi-domain inhibitor revealed to have an excellent pharmacokinetics profile thus likely to have safe and effective therapeutic applications for the future. Molecular dynamics simulation in aqueous solution further supported the high affinity of the compound for the target site involving strong hydrogen bonding. At residue level, radial distribution function (RDF) and axial distribution function (AFD) illustrated Asp334 as the most critical amino acid that drives recognition, binding, and activity of the compound. The complex stability was validated by subjecting it to Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA), Molecular Mechanics Generalized Born Surface Area (MMGBSA) and WaterSwap based binding free energy calculations. The system was observed with high stability: total binding energy in MMGBSA (−48.45 kcal/mol) and MMPBSA (−3.62 kcal/mol). The columbic interactions were noticed to dominate (−336.90 kcal/mol), followed by van der Waals energies (−45.52 kcal/mol) in MurC-inhibitor binding. The absolute binding free energy estimated by WaterSwap was −43.2 kcal/mol, depicting higher complex stability. The screened scaffold might be used in functional groups substitution to achieve further lead optimization.