Sidra Abbas , Shama Mujawar , Azra Yasmin , Shaghufta Perveen , Parvez Azam Malik , Muhammad Shoaib Ali Gill , Tahir Ali Chohan
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引用次数: 0
Abstract
Pseudomonas aeruginosa is a major pathogen in clinical settings, notorious for its intrinsic resistance to multiple antibiotics and ability to form biofilms, therefore, complicating treatment. This study reporting the results of a high-throughput screen of an antibacterial library targeting LasR, a key QS regulator in P. aeruginosa MB638, isolated from an infected surgical implant. The species identity was confirmed as P. aeruginosa via 16S rDNA analysis (accession number MT643188). The strain demonstrated strong biofilm formation and multidrug resistance, along with significant production of the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). We screened a ∼1400-compound library and identified inhibitors compounds that surpass the binding affinity of LasR’s native ligand. The ADMET analysis revealed that among these, compounds Inh-1, Inh-2 and Inh-3 demonstrated favourable absorption, permeability and broader bioactivity profiles. Inh-1 exhibited a suitable profile, being non-toxic, non-hepatotoxic, and non-mutagenic, with low carcinogenic and immunotoxin potential. Molecular docking studies using GLIDE identified key binding interactions and residues within the LasR ligand-binding domain (LBD), with Inh-1, Inh-2 and Inh-3 showing the highest binding affinities and favourable docking scores of −14.587, −13.645 and −12.967, respectively. Structural Interaction Molecular dynamics simulation at 100 ns showed Inh-1 maintained stable hydrophobic and hydrophilic contacts within the active site. RMSD analysis confirmed the stability of the Inh-1 complex, while RMSF indicated conformational adaptability. Inh-1 stands out as promising lead for LasR inhibition, warranting further experimental study. These inhibitors hold promise for disrupting quorum sensing in P. aeruginosa and may serve as potential therapeutic agent against resistant infections.
期刊介绍:
Computational Biology and Chemistry publishes original research papers and review articles in all areas of computational life sciences. High quality research contributions with a major computational component in the areas of nucleic acid and protein sequence research, molecular evolution, molecular genetics (functional genomics and proteomics), theory and practice of either biology-specific or chemical-biology-specific modeling, and structural biology of nucleic acids and proteins are particularly welcome. Exceptionally high quality research work in bioinformatics, systems biology, ecology, computational pharmacology, metabolism, biomedical engineering, epidemiology, and statistical genetics will also be considered.
Given their inherent uncertainty, protein modeling and molecular docking studies should be thoroughly validated. In the absence of experimental results for validation, the use of molecular dynamics simulations along with detailed free energy calculations, for example, should be used as complementary techniques to support the major conclusions. Submissions of premature modeling exercises without additional biological insights will not be considered.
Review articles will generally be commissioned by the editors and should not be submitted to the journal without explicit invitation. However prospective authors are welcome to send a brief (one to three pages) synopsis, which will be evaluated by the editors.