Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses
Abstract Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Sa...
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| Format: | Article |
| Language: | English |
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BMC
2023-01-01
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| Series: | BMC Microbiology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12866-023-02756-6 |
| _version_ | 1797946043775582208 |
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| author | Muneeba Afzal Syed Shah Hassan Saman Sohail Ihosvany Camps Yasmin Khan Zarrin Basharat Asad Karim Muhammad Aurongzeb Muhammad Irfan Muhammad Salman Carlos M. Morel |
| author_facet | Muneeba Afzal Syed Shah Hassan Saman Sohail Ihosvany Camps Yasmin Khan Zarrin Basharat Asad Karim Muhammad Aurongzeb Muhammad Irfan Muhammad Salman Carlos M. Morel |
| author_sort | Muneeba Afzal |
| collection | DOAJ |
| description | Abstract Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Salmonella Typhi and the complete genomes of eight strains were primarily subjected to the EDGAR tool to predict the core genome (n = 3207). Human non-homology (n = 2450) was followed by essential genes identification (n = 37). The STRING database predicted maximum protein-protein interactions, followed by cellular localization. The virulent/immunogenic ability of predicted genes were checked to differentiate drug and vaccine targets. Furthermore, the 3D models of the identified putative proteins encoded by the respective genes were constructed and subjected to druggability analyses where only “highly druggable” proteins were selected for molecular docking and simulation analyses. The putative targets ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol phosphate synthase hisH, 7,8-dihydropteroate synthase folP and 2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI were screened against a drug-like library (n = 12,000) and top hits were selected based on H-bonds, RMSD and energy scores. Finally, the ADMET properties for novel inhibitors ZINC19340748, ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by binding free energy (MM/PBSA) calculation for ligand-receptor complexes. The findings of this work are expected to aid in expediting the identification of novel protein targets and inhibitors in combating typhoid Salmonellosis, in addition to the already existing therapies. |
| first_indexed | 2024-04-10T21:04:40Z |
| format | Article |
| id | doaj.art-c54f36acc7a445d593dd07dd4dbb713b |
| institution | Directory Open Access Journal |
| issn | 1471-2180 |
| language | English |
| last_indexed | 2024-04-10T21:04:40Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Microbiology |
| spelling | doaj.art-c54f36acc7a445d593dd07dd4dbb713b2023-01-22T12:06:08ZengBMCBMC Microbiology1471-21802023-01-0123112010.1186/s12866-023-02756-6Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analysesMuneeba Afzal0Syed Shah Hassan1Saman Sohail2Ihosvany Camps3Yasmin Khan4Zarrin Basharat5Asad Karim6Muhammad Aurongzeb7Muhammad Irfan8Muhammad Salman9Carlos M. Morel10Department of Health and Biological Sciences, Abasyn University PeshawarDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDepartment of Chemistry, Islamia College PeshawarLaboratório de Modelagem Computacional, LaModel, Instituto de Ciências Exatas - ICEx. Universidade Federal de Alfenas - UNIFAL-MGDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of KarachiDepartment of Health and Biological Sciences, Abasyn University PeshawarCentre for Technological Development in Health (CDTS), Oswaldo Cruz Foundation (Fiocruz)Abstract Typhoid fever is transmitted by ingestion of polluted water, contaminated food, and stool of typhoid-infected individuals, mostly in developing countries with poor hygienic environments. To find novel therapeutic targets and inhibitors, We employed a subtractive genomics strategy towards Salmonella Typhi and the complete genomes of eight strains were primarily subjected to the EDGAR tool to predict the core genome (n = 3207). Human non-homology (n = 2450) was followed by essential genes identification (n = 37). The STRING database predicted maximum protein-protein interactions, followed by cellular localization. The virulent/immunogenic ability of predicted genes were checked to differentiate drug and vaccine targets. Furthermore, the 3D models of the identified putative proteins encoded by the respective genes were constructed and subjected to druggability analyses where only “highly druggable” proteins were selected for molecular docking and simulation analyses. The putative targets ATP-dependent CLP protease proteolytic subunit, Imidazole glycerol phosphate synthase hisH, 7,8-dihydropteroate synthase folP and 2,3-bisphosphoglycerate-independent phosphoglycerate mutase gpmI were screened against a drug-like library (n = 12,000) and top hits were selected based on H-bonds, RMSD and energy scores. Finally, the ADMET properties for novel inhibitors ZINC19340748, ZINC09319798, ZINC00494142, ZINC32918650 were optimized followed by binding free energy (MM/PBSA) calculation for ligand-receptor complexes. The findings of this work are expected to aid in expediting the identification of novel protein targets and inhibitors in combating typhoid Salmonellosis, in addition to the already existing therapies.https://doi.org/10.1186/s12866-023-02756-6Salmonella TyphiSubtractive genomicsScreening and ADMET profilingMD simulation |
| spellingShingle | Muneeba Afzal Syed Shah Hassan Saman Sohail Ihosvany Camps Yasmin Khan Zarrin Basharat Asad Karim Muhammad Aurongzeb Muhammad Irfan Muhammad Salman Carlos M. Morel Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses BMC Microbiology Salmonella Typhi Subtractive genomics Screening and ADMET profiling MD simulation |
| title | Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses |
| title_full | Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses |
| title_fullStr | Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses |
| title_full_unstemmed | Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses |
| title_short | Genomic landscape of the emerging XDR Salmonella Typhi for mining druggable targets clpP, hisH, folP and gpmI and screening of novel TCM inhibitors, molecular docking and simulation analyses |
| title_sort | genomic landscape of the emerging xdr salmonella typhi for mining druggable targets clpp hish folp and gpmi and screening of novel tcm inhibitors molecular docking and simulation analyses |
| topic | Salmonella Typhi Subtractive genomics Screening and ADMET profiling MD simulation |
| url | https://doi.org/10.1186/s12866-023-02756-6 |
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