Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)

Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, <i>Pseudomonas aer...

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Autores principales:	Raed A. H. Almihyawi, Halah M. H. Al-Hasani, Tabarak Sabah Jassim, Ziyad Tariq Muhseen, Sitong Zhang, Guang Chen
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Pseudomonas aeruginosa</i> multiple virulence factor regulator asinex antibacterial library comprehensive marine natural products database M64 control binding free energies Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/f52179035cc24bda94e12e09231cb746
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spelling	oai:doaj.org-article:f52179035cc24bda94e12e09231cb7462021-11-25T18:27:26ZMolecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)10.3390/molecules262268111420-3049https://doaj.org/article/f52179035cc24bda94e12e09231cb7462021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/6811https://doaj.org/toc/1420-3049Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, <i>Pseudomonas aeruginosa</i>, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis <i>P. aeruginosa</i> by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.Raed A. H. AlmihyawiHalah M. H. Al-HasaniTabarak Sabah JassimZiyad Tariq MuhseenSitong ZhangGuang ChenMDPI AGarticle<i>Pseudomonas aeruginosa</i>multiple virulence factor regulatorasinex antibacterial librarycomprehensive marine natural products databaseM64 controlbinding free energiesOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6811, p 6811 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Pseudomonas aeruginosa</i> multiple virulence factor regulator asinex antibacterial library comprehensive marine natural products database M64 control binding free energies Organic chemistry QD241-441
spellingShingle	<i>Pseudomonas aeruginosa</i> multiple virulence factor regulator asinex antibacterial library comprehensive marine natural products database M64 control binding free energies Organic chemistry QD241-441 Raed A. H. Almihyawi Halah M. H. Al-Hasani Tabarak Sabah Jassim Ziyad Tariq Muhseen Sitong Zhang Guang Chen Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
description	Multi-drug resistance (MDR) bacterial pathogens pose a threat to global health and warrant the discovery of new therapeutic molecules, particularly those that can neutralize their virulence and stop the evolution of new resistant mechanisms. The superbug nosocomial pathogen, <i>Pseudomonas aeruginosa</i>, uses a multiple virulence factor regulator (MvfR) to regulate the expression of multiple virulence proteins during acute and persistent infections. The present study targeted MvfR with the intention of designing novel anti-virulent compounds, which will function in two ways: first, they will block the virulence and pathogenesis <i>P. aeruginosa</i> by disrupting the quorum-sensing network of the bacteria, and second, they will stop the evolution of new resistant mechanisms. A structure-based virtual screening (SBVS) method was used to screen druglike compounds from the Asinex antibacterial library (~5968 molecules) and the comprehensive marine natural products database (CMNPD) (~32 thousand compounds), against the ligand-binding domain (LBD) of MvfR, to identify molecules that show high binding potential for the relevant pocket. In this way, two compounds were identified: Top-1 (4-((carbamoyloxy)methyl)-10,10-dihydroxy-2,6-diiminiodecahydropyrrolo[1,2-c]purin-9-yl sulfate) and Top-2 (10,10-dihydroxy-2,6-diiminio-4-(((sulfonatocarbamoyl)oxy)methyl)decahydropyrrolo[1,2-c]purin-9-yl sulfate), in contrast to the co-crystallized M64 control. Both of the screened leads were found to show deep pocket binding and interactions with several key residues through a network of hydrophobic and hydrophilic interactions. The docking results were validated by a long run of 200 ns of molecular dynamics simulation and MM-PB/GBSA binding free energies. All of these analyses confirmed the presence of strong complex formation and rigorous intermolecular interactions. An additional analysis of normal mode entropy and a WaterSwap assay were also performed to complement the aforementioned studies. Lastly, the compounds were found to show an acceptable range of pharmacokinetic properties, making both compounds potential candidates for further experimental studies to decipher their real biological potency.
format	article
author	Raed A. H. Almihyawi Halah M. H. Al-Hasani Tabarak Sabah Jassim Ziyad Tariq Muhseen Sitong Zhang Guang Chen
author_facet	Raed A. H. Almihyawi Halah M. H. Al-Hasani Tabarak Sabah Jassim Ziyad Tariq Muhseen Sitong Zhang Guang Chen
author_sort	Raed A. H. Almihyawi
title	Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
title_short	Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
title_full	Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
title_fullStr	Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
title_full_unstemmed	Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)
title_sort	molecular insights into binding mode and interactions of structure-based virtually screened inhibitors for <i>pseudomonas aeruginosa</i> multiple virulence factor regulator (mvfr)
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f52179035cc24bda94e12e09231cb746
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Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for <i>Pseudomonas aeruginosa</i> Multiple Virulence Factor Regulator (MvfR)

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