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Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors Using Pharmacophore-Based Approach

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Department of Pathophysiology, The Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Guangdong 515031, China
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Department of physiology, Shantou University Medical College, Guangdong 515031, China
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Department of organic and biomolecular chemistry, Ural Federal University, Yekaterinburg 620002, Russia
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Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(2), 266; https://doi.org/10.3390/biom10020266
Received: 12 December 2019 / Revised: 5 February 2020 / Accepted: 6 February 2020 / Published: 10 February 2020
Multidrug resistance in Pseudomonas aeruginosa is a noticeable and ongoing major obstacle for inhibitor design. In P. aeruginosa, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) acetyltransferase (PaLpxA) is an essential enzyme of lipid A biosynthesis and an attractive drug target. PaLpxA is a homotrimer, and the binding pocket for its substrate, UDP-GlcNAc, is positioned between the monomer A–monomer B interface. The uracil moiety binds at one monomer A, the GlcNAc moiety binds at another monomer B, and a diphosphate form bonds with both monomers. The catalytic residues are conserved and display a similar catalytic mechanism across orthologs, but some distinctions exist between pocket sizes, residue differences, substrate positioning and specificity. The analysis of diversified pockets, volumes, and ligand positions was determined between orthologues that could aid in selective inhibitor development. Thenceforth, a complex-based pharmacophore model was generated and subjected to virtual screening to identify compounds with similar pharmacophoric properties. Docking and general Born-volume integral (GBVI) studies demonstrated 10 best lead compounds with selective inhibition properties with essential residues in the pocket. For biological access, these scaffolds complied with the Lipinski rule, no toxicity and drug likeness properties, and were considered as lead compounds. Hence, these scaffolds could be helpful for the development of potential selective PaLpxA inhibitors.
Keywords: PaLpxA; docking; pharmacophore; virtual screening; GBVI; ADME PaLpxA; docking; pharmacophore; virtual screening; GBVI; ADME
MDPI and ACS Style

Bhaskar, B.V.; Babu, T.M.C.; Rammohan, A.; Zheng, G.Y.; Zyryanov, G.V.; Gu, W. Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors Using Pharmacophore-Based Approach. Biomolecules 2020, 10, 266.

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