A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development
Abstract Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibioti...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-57702-x |
| _version_ | 1797233689260720128 |
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| author | Amneh Shtaiwi Shafi Ullah Khan Meriem Khedraoui Mohd Alaraj Abdelouahid Samadi Samir Chtita |
| author_facet | Amneh Shtaiwi Shafi Ullah Khan Meriem Khedraoui Mohd Alaraj Abdelouahid Samadi Samir Chtita |
| author_sort | Amneh Shtaiwi |
| collection | DOAJ |
| description | Abstract Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibiotic therapy. Many MurG inhibitors have been recognized as MurG targets, but high toxicity and drug-resistant Escherichia coli strains remain the most important problems for further development. In addition, the discovery of selective MurG inhibitors has been limited to the synthesis of peptidoglycan-mimicking compounds. The present study employed drug discovery, such as virtual screening using molecular docking, drug likeness ADMET proprieties predictions, and molecular dynamics (MD) simulation, to identify potential natural products (NPs) for Escherichia coli. We conducted a screening of 30,926 NPs from the NPASS database. Subsequently, 20 of these compounds successfully passed the potency, pharmacokinetic, ADMET screening assays, and their validation was further confirmed through molecular docking. The best three hits and the standard were chosen for further MD simulations up to 400 ns and energy calculations to investigate the stability of the NPs-MurG complexes. The analyses of MD simulations and total binding energies suggested the higher stability of NPC272174. The potential compounds can be further explored in vivo and in vitro for promising novel antibacterial drug discovery. |
| first_indexed | 2024-04-24T16:20:10Z |
| format | Article |
| id | doaj.art-aba60eb070e14f04b507a4c453790b25 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T16:20:10Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-aba60eb070e14f04b507a4c453790b252024-03-31T11:14:57ZengNature PortfolioScientific Reports2045-23222024-03-0114111710.1038/s41598-024-57702-xA comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug developmentAmneh Shtaiwi0Shafi Ullah Khan1Meriem Khedraoui2Mohd Alaraj3Abdelouahid Samadi4Samir Chtita5Faculty of Pharmacy, Middle East UniversityInterdisciplinary Research Unit for Cancer Prevention and Treatment, Baclesse Cancer Centre, Université de Caen Normandie Inserm Anticipe UMR 1086, Normandie UnivLaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of CasablancaFaculty of Pharmacy, University of JerashDepartment of Chemistry, College of Science, UAEULaboratory of Analytical and Molecular Chemistry, Faculty of Sciences Ben M’Sik, Hassan II University of CasablancaAbstract Peptidoglycan is a carbohydrate with a cross-linked structure that protects the cytoplasmic membrane of bacterial cells from damage. The mechanism of peptidoglycan biosynthesis involves the main synthesizing enzyme glycosyltransferase MurG, which is known as a potential target for antibiotic therapy. Many MurG inhibitors have been recognized as MurG targets, but high toxicity and drug-resistant Escherichia coli strains remain the most important problems for further development. In addition, the discovery of selective MurG inhibitors has been limited to the synthesis of peptidoglycan-mimicking compounds. The present study employed drug discovery, such as virtual screening using molecular docking, drug likeness ADMET proprieties predictions, and molecular dynamics (MD) simulation, to identify potential natural products (NPs) for Escherichia coli. We conducted a screening of 30,926 NPs from the NPASS database. Subsequently, 20 of these compounds successfully passed the potency, pharmacokinetic, ADMET screening assays, and their validation was further confirmed through molecular docking. The best three hits and the standard were chosen for further MD simulations up to 400 ns and energy calculations to investigate the stability of the NPs-MurG complexes. The analyses of MD simulations and total binding energies suggested the higher stability of NPC272174. The potential compounds can be further explored in vivo and in vitro for promising novel antibacterial drug discovery.https://doi.org/10.1038/s41598-024-57702-xMurGNatural productsAntibacterialAntibiotics resistanceVirtual screeningMolecular dynamics |
| spellingShingle | Amneh Shtaiwi Shafi Ullah Khan Meriem Khedraoui Mohd Alaraj Abdelouahid Samadi Samir Chtita A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development Scientific Reports MurG Natural products Antibacterial Antibiotics resistance Virtual screening Molecular dynamics |
| title | A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development |
| title_full | A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development |
| title_fullStr | A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development |
| title_full_unstemmed | A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development |
| title_short | A comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase MurG in Escherichia coli for potential drug development |
| title_sort | comprehensive computational study to explore promising natural bioactive compounds targeting glycosyltransferase murg in escherichia coli for potential drug development |
| topic | MurG Natural products Antibacterial Antibiotics resistance Virtual screening Molecular dynamics |
| url | https://doi.org/10.1038/s41598-024-57702-x |
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