Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery
Tuberculosis, caused by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in <i>M. tuberculosis</i> bro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/9/11/819 |
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| author | Hamza Arshad Dar Tahreem Zaheer Nimat Ullah Syeda Marriam Bakhtiar Tianyu Zhang Muhammad Yasir Esam I. Azhar Amjad Ali |
| author_facet | Hamza Arshad Dar Tahreem Zaheer Nimat Ullah Syeda Marriam Bakhtiar Tianyu Zhang Muhammad Yasir Esam I. Azhar Amjad Ali |
| author_sort | Hamza Arshad Dar |
| collection | DOAJ |
| description | Tuberculosis, caused by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in <i>M. tuberculosis</i> broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of <i>M. tuberculosis</i> has provided an opportunity to explore the pangenome of the species along with the pan-phylogeny and to identify potential novel drug targets leading to drug discovery. We attempt to calculate the pangenome of <i>M. tuberculosis</i> that comprises a total of 150 complete genomes and performed the phylo-genomic classification and analysis. Further, the conserved core genome (1251 proteins) is subjected to various sequential filters (non-human homology, essentiality, virulence, physicochemical parameters, and pathway analysis) resulted in identification of eight putative broad-spectrum drug targets. Upon molecular docking analyses of these targets with ligands available at the DrugBank database shortlisted a total of five promising ligands with projected inhibitory potential; namely, 2′deoxy-thymidine-5′-diphospho-alpha-<span style="font-variant: small-caps;">d</span>-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-<span style="font-variant: small-caps;">l</span>-rhamnose, thymidine-5′-triphosphate, and citicoline. We are confident that with further lead optimization and experimental validation, these lead compounds may provide a sound basis to develop safe and effective drugs against tuberculosis disease in humans. |
| first_indexed | 2024-03-10T14:46:48Z |
| format | Article |
| id | doaj.art-70a1353983c1424cb62e109c2d4cf798 |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-10T14:46:48Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-70a1353983c1424cb62e109c2d4cf7982023-11-20T21:17:13ZengMDPI AGAntibiotics2079-63822020-11-0191181910.3390/antibiotics9110819Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug DiscoveryHamza Arshad Dar0Tahreem Zaheer1Nimat Ullah2Syeda Marriam Bakhtiar3Tianyu Zhang4Muhammad Yasir5Esam I. Azhar6Amjad Ali7Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, PakistanAtta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, PakistanDepartment of Bioinformatics and Biosciences, Capital University of Science and Technology Islamabad expressway, Kahuta Road, Zone-V, Islamabad 44000, PakistanState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou 510530, ChinaSpecial Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi ArabiaSpecial Infectious Agents Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi ArabiaAtta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, PakistanTuberculosis, caused by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>), is one of the leading causes of human deaths globally according to the WHO TB 2019 report. The continuous rise in multi- and extensive-drug resistance in <i>M. tuberculosis</i> broadens the challenges to control tuberculosis. The availability of a large number of completely sequenced genomes of <i>M. tuberculosis</i> has provided an opportunity to explore the pangenome of the species along with the pan-phylogeny and to identify potential novel drug targets leading to drug discovery. We attempt to calculate the pangenome of <i>M. tuberculosis</i> that comprises a total of 150 complete genomes and performed the phylo-genomic classification and analysis. Further, the conserved core genome (1251 proteins) is subjected to various sequential filters (non-human homology, essentiality, virulence, physicochemical parameters, and pathway analysis) resulted in identification of eight putative broad-spectrum drug targets. Upon molecular docking analyses of these targets with ligands available at the DrugBank database shortlisted a total of five promising ligands with projected inhibitory potential; namely, 2′deoxy-thymidine-5′-diphospho-alpha-<span style="font-variant: small-caps;">d</span>-glucose, uridine diphosphate glucose, 2′-deoxy-thymidine-beta-<span style="font-variant: small-caps;">l</span>-rhamnose, thymidine-5′-triphosphate, and citicoline. We are confident that with further lead optimization and experimental validation, these lead compounds may provide a sound basis to develop safe and effective drugs against tuberculosis disease in humans.https://www.mdpi.com/2079-6382/9/11/819<i>Mycobacterium tuberculosis</i>pangenomedrug targetsmolecular dockinglead compoundsdrug discovery |
| spellingShingle | Hamza Arshad Dar Tahreem Zaheer Nimat Ullah Syeda Marriam Bakhtiar Tianyu Zhang Muhammad Yasir Esam I. Azhar Amjad Ali Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery Antibiotics <i>Mycobacterium tuberculosis</i> pangenome drug targets molecular docking lead compounds drug discovery |
| title | Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery |
| title_full | Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery |
| title_fullStr | Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery |
| title_full_unstemmed | Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery |
| title_short | Pangenome Analysis of <i>Mycobacterium tuberculosis</i> Reveals Core-Drug Targets and Screening of Promising Lead Compounds for Drug Discovery |
| title_sort | pangenome analysis of i mycobacterium tuberculosis i reveals core drug targets and screening of promising lead compounds for drug discovery |
| topic | <i>Mycobacterium tuberculosis</i> pangenome drug targets molecular docking lead compounds drug discovery |
| url | https://www.mdpi.com/2079-6382/9/11/819 |
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