Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae
Published on Sep 1, 2019in Interdisciplinary Sciences: Computational Life Sciences1.42
· DOI :10.1007/s12539-018-0299-y
The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3-hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K. pneumoniae LpxC (KpLpxC) topology distinct from its orthologous counterparts in other bacterial species. Molecular docking study of the protein recognized receptor antagonist compound 106, a uridine-based LpxC inhibitory compound, as a ligand best able to fit the binding pocket with a Gold Score of 67.53. Molecular dynamics simulation of docked KpLpxC revealed an alternate binding pattern of ligand in the active site. The ligand tail exhibited preferred binding to the domain I residues as opposed to the substrate binding hydrophobic channel of subdomain II, usually targeted by inhibitory compounds. Comparison with the undocked KpLpxC system demonstrated ligand induced high conformational changes in the hydrophobic channel of subdomain II in KpLpxC. Hence, ligand exerted its inhibitory potential by rendering the channel unstable for substrate binding.