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

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...

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Autores principales: Bhaskar, Baki Vijaya, Babu, Tirumalasetty Muni Chandra, Rammohan, Aluru, Zheng, Gui Yu, Zyryanov, Grigory V., Gu, Wei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072397/
https://www.ncbi.nlm.nih.gov/pubmed/32050706
http://dx.doi.org/10.3390/biom10020266
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author Bhaskar, Baki Vijaya
Babu, Tirumalasetty Muni Chandra
Rammohan, Aluru
Zheng, Gui Yu
Zyryanov, Grigory V.
Gu, Wei
author_facet Bhaskar, Baki Vijaya
Babu, Tirumalasetty Muni Chandra
Rammohan, Aluru
Zheng, Gui Yu
Zyryanov, Grigory V.
Gu, Wei
author_sort Bhaskar, Baki Vijaya
collection PubMed
description 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.
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spelling pubmed-70723972020-03-19 Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach Bhaskar, Baki Vijaya Babu, Tirumalasetty Muni Chandra Rammohan, Aluru Zheng, Gui Yu Zyryanov, Grigory V. Gu, Wei Biomolecules Article 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. MDPI 2020-02-10 /pmc/articles/PMC7072397/ /pubmed/32050706 http://dx.doi.org/10.3390/biom10020266 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bhaskar, Baki Vijaya
Babu, Tirumalasetty Muni Chandra
Rammohan, Aluru
Zheng, Gui Yu
Zyryanov, Grigory V.
Gu, Wei
Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title_full Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title_fullStr Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title_full_unstemmed Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title_short Structure-Based Virtual Screening of Pseudomonas aeruginosa LpxA Inhibitors using Pharmacophore-Based Approach
title_sort structure-based virtual screening of pseudomonas aeruginosa lpxa inhibitors using pharmacophore-based approach
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072397/
https://www.ncbi.nlm.nih.gov/pubmed/32050706
http://dx.doi.org/10.3390/biom10020266
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