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

التفاصيل البيبلوغرافية
العنوان: Molecular Insights into Binding Mode and Interactions of Structure-Based Virtually Screened Inhibitors for Pseudomonas aeruginosa Multiple Virulence Factor Regulator (MvfR)
المؤلفون: Tabarak Sabah Jassim, Sitong Zhang, Halah M H Al-Hasani, Ziyad Tariq Muhseen, Raed A H Almihyawi, Guang Chen
المصدر: Molecules, Vol 26, Iss 6811, p 6811 (2021)
Molecules
Volume 26
Issue 22
بيانات النشر: MDPI AG, 2021.
سنة النشر: 2021
مصطلحات موضوعية: Databases, Pharmaceutical, Virulence Factors, Regulator, Drug Evaluation, Preclinical, Pharmaceutical Science, Virulence, Organic chemistry, Computational biology, Microbial Sensitivity Tests, Molecular Dynamics Simulation, medicine.disease_cause, Ligands, asinex antibacterial library, Virulence factor, Article, Analytical Chemistry, Small Molecule Libraries, User-Computer Interface, QD241-441, Bacterial Proteins, Drug Resistance, Multiple, Bacterial, Drug Discovery, medicine, Humans, Physical and Theoretical Chemistry, comprehensive marine natural products database, M64 control, binding free energies, Virtual screening, Binding Sites, biology, Pseudomonas aeruginosa, Chemistry, Hydrogen Bonding, biology.organism_classification, Anti-Bacterial Agents, multiple virulence factor regulator, Chemistry (miscellaneous), Docking (molecular), Drug Design, Molecular Medicine, Hydrophobic and Hydrophilic Interactions, Function (biology), Bacteria
الوصف: 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, Pseudomonas aeruginosa, 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 P. aeruginosa 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.
وصف الملف: application/pdf
اللغة: English
تدمد: 1420-3049
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::43e95922e3f6608bc3af524b9c5c6d26
https://www.mdpi.com/1420-3049/26/22/6811
حقوق: OPEN
رقم الأكسشن: edsair.doi.dedup.....43e95922e3f6608bc3af524b9c5c6d26
قاعدة البيانات: OpenAIRE