Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation
Currently, the treatment of <i>Proteus mirabilis</i> infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS),...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-09-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/16/9/1263 |
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| author | Samar S. Elbaramawi Ahmed G. Eissa Nada A. Noureldin Claire Simons |
| author_facet | Samar S. Elbaramawi Ahmed G. Eissa Nada A. Noureldin Claire Simons |
| author_sort | Samar S. Elbaramawi |
| collection | DOAJ |
| description | Currently, the treatment of <i>Proteus mirabilis</i> infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for <i>P. mirabilis</i> MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for <i>P. mirabilis</i> MetRS using <i>Escherichia coli</i> MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against <i>P. mirabilis</i>. |
| first_indexed | 2024-03-10T22:17:21Z |
| format | Article |
| id | doaj.art-e521180828e5480ea93fb241af350f9e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T22:17:21Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-e521180828e5480ea93fb241af350f9e2023-11-19T12:24:52ZengMDPI AGPharmaceuticals1424-82472023-09-01169126310.3390/ph16091263Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking ValidationSamar S. Elbaramawi0Ahmed G. Eissa1Nada A. Noureldin2Claire Simons3Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptDepartment of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptDepartment of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptSchool of Pharmacy & Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UKCurrently, the treatment of <i>Proteus mirabilis</i> infections is considered to be complicated as the organism has become resistant to numerous antibiotic classes. Therefore, new inhibitors should be developed, targeting bacterial molecular functions. Methionine tRNA synthetase (MetRS), a member of the aminoacyl-tRNA synthetase family, is essential for protein biosynthesis offering a promising target for novel antibiotics discovery. In the context of computer-aided drug design (CADD), the current research presents the construction and analysis of a comparative homology model for <i>P. mirabilis</i> MetRS, enabling development of novel inhibitors with greater selectivity. Molecular Operating Environment (MOE) software was used to build a homology model for <i>P. mirabilis</i> MetRS using <i>Escherichia coli</i> MetRS as a template. The model was evaluated, and the active site of the target protein predicted from its sequence using conservation analysis. Molecular dynamic simulations were performed to evaluate the stability of the modeled protein structure. In order to evaluate the predicted active site interactions, methionine (the natural substrate of MetRS) and several inhibitors of bacterial MetRS were docked into the constructed model using MOE. After validation of the model, pharmacophore-based virtual screening for a systemically prepared dataset of compounds was performed to prove the feasibility of the proposed model, identifying possible parent compounds for further development of MetRS inhibitors against <i>P. mirabilis</i>.https://www.mdpi.com/1424-8247/16/9/1263<i>Proteus mirabilis</i>homology modelmethionyl tRNA synthetasevirtual screeningurinary tract infectionsmolecular dynamics |
| spellingShingle | Samar S. Elbaramawi Ahmed G. Eissa Nada A. Noureldin Claire Simons Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation Pharmaceuticals <i>Proteus mirabilis</i> homology model methionyl tRNA synthetase virtual screening urinary tract infections molecular dynamics |
| title | Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation |
| title_full | Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation |
| title_fullStr | Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation |
| title_full_unstemmed | Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation |
| title_short | Exploring <i>Proteus mirabilis</i> Methionine tRNA Synthetase Active Site: Homology Model Construction, Molecular Dynamics, Pharmacophore and Docking Validation |
| title_sort | exploring i proteus mirabilis i methionine trna synthetase active site homology model construction molecular dynamics pharmacophore and docking validation |
| topic | <i>Proteus mirabilis</i> homology model methionyl tRNA synthetase virtual screening urinary tract infections molecular dynamics |
| url | https://www.mdpi.com/1424-8247/16/9/1263 |
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