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Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae

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Abstract

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.

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Acknowledgements

Authors are highly grateful to the Pakistan-United States Science and Technology Cooperation Program for granting the financial assistance.

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Authors and Affiliations

  1. National Center for Bioinformatics (NCB), Quaid-i-Azam University, Islamabad, 45320, Pakistan

    Sajjad Ahmad, Afifa Navid, Amina Saleem Akhtar & Syed Sikander Azam

  2. Department of Biochemistry, Abdul Wali Khan University-Mardan, Shankar Campus, Mardan, Khyber Pukhtoonkhwa, Pakistan

    Abdul Wadood

  3. Structural Bioinformatics and High Performance Computing Research Group (BIO-HPC), Universidad Católica San Antonio de Murcia (UCAM), Murcia, Spain

    Horacio Pérez-Sánchez

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  1. Sajjad Ahmad
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  2. Afifa Navid
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Electronic supplementary material

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12539_2018_299_MOESM1_ESM.docx

Table Sl-1 DrugBank features of essential, druggable targets and their predicted sub cellular localizations (DOCX 11 KB)

12539_2018_299_MOESM2_ESM.pdf

Table SI-2 Chemical structure, GOLD scores and AutoDock Vina acquired binding affinities (kJ mol−1) of 249 docked compounds (PDF 733 KB)

12539_2018_299_MOESM3_ESM.docx

Table SI-3 Zn coordination dynamics observed in undocked and docked KpLpxC systems over 12 and 30 ns simulations, respectively (DOCX 12 KB)

12539_2018_299_MOESM4_ESM.tif

Fig. SI-1 Distribution of 204 pathogen-specific, essential proteins in 37 unique metabolic pathways of K. pneumoniae HS11286 (TIF 2052 KB)

Fig. SI-2 Local model quality plot for top modelled KpLpxC (JPG 26 KB)

12539_2018_299_MOESM6_ESM.tif

Fig. SI-3 Multiple sequence alignment of KpLpxC against PaLpxC, YeLpxC and EcLpxC for active site prediction (TIF 4957 KB)

12539_2018_299_MOESM7_ESM.tif

Fig. SI-4 Superimposed RMSD, RMSF and β-Factor graphs of undocked and docked KpLpxC systems after 12 ns simulations (TIF 7102 KB)

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Ahmad, S., Navid, A., Akhtar, A.S. et al. Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae. Interdiscip Sci Comput Life Sci 11, 508–526 (2019). https://doi.org/10.1007/s12539-018-0299-y

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