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

Abstract

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.

Emergence of Colistin-Resistant Acinetobacter junii in China

“…The crystal structures and binding domains of LpxA and LpxD in A. baumannii have been thoroughly investigated. The LpxA amino acid substitutions sites Ile107 and His131 were inside the UDP-binding Pocket, while the His131 was located near the crucial residue Ile133, which might affect its UDP combination and interfere with its function [ 21 , 22 ]. The LpxD amino acid substitution sites Phe20 and Lys263 are located in the uridine-binding and lipid-binding domains, respectively, leading to a possible impact on enzyme function and polymerization [ 20 ].…”

Molecular insight into isoform specific inhibition of PI3K-α and PKC-η with dietary agents through an ensemble pharmacophore and docking studies

“…Furthermore, to avoid errors in compound structures, for instance, single bonds, protonation, disordered bond lengths, tautomers, ionization states, and explicit counter ions, in this connection, the database was launched into MOE to remove faulty structures by washing. Energy minimization was achieved with 3D optimization of small molecules and the addition of hydrogens and atomic partial charges with MMFF94x forcefield 55 . Finally, the refined small molecules were examined in subsequent studies.…”

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii – A computational study

“…The study details that compound 1 binds competitively to the apoprotein while compound 2 binds to the LpxA/Product complex ( Han et al., 2020 ). Other studies from P. aeruginosa LpxA utilize in-silico techniques to identify inhibitors via pharmacophore modelling yet do not include in vitro validation ( Bhaskar et al., 2020 ).

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