Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i>
Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) <i>Mycobacterium tuberculosis</i> (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a foc...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-09-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/12/10/1356 |
| _version_ | 1797474956322275328 |
|---|---|
| author | Leena Hussein Bajrai Aiah M. Khateb Maha M. Alawi Hashim R. Felemban Anees A. Sindi Vivek Dhar Dwivedi Esam Ibraheem Azhar |
| author_facet | Leena Hussein Bajrai Aiah M. Khateb Maha M. Alawi Hashim R. Felemban Anees A. Sindi Vivek Dhar Dwivedi Esam Ibraheem Azhar |
| author_sort | Leena Hussein Bajrai |
| collection | DOAJ |
| description | Due to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) <i>Mycobacterium tuberculosis</i> (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains. |
| first_indexed | 2024-03-09T20:38:17Z |
| format | Article |
| id | doaj.art-ca57ebcbfe9841fead6689545bca2565 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T20:38:17Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-ca57ebcbfe9841fead6689545bca25652023-11-23T23:07:25ZengMDPI AGBiomolecules2218-273X2022-09-011210135610.3390/biom12101356Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i>Leena Hussein Bajrai0Aiah M. Khateb1Maha M. Alawi2Hashim R. Felemban3Anees A. Sindi4Vivek Dhar Dwivedi5Esam Ibraheem Azhar6Special Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaBioinformatics Research Division, Quanta Calculus Pvt. Ltd., Greater Noida 201310, IndiaSpecial Infectious Agents Unit-BSL3, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21362, Saudi ArabiaDue to the concerning rise in the number of multiple- and prolonged-drug-resistant (MDR and XDR) <i>Mycobacterium tuberculosis</i> (Mtb) strains, unprecedented demand has been created to design and develop novel therapeutic drugs with higher efficacy and safety. In this study, with a focused view on implementing an in silico drug design pipeline, a diverse set of glycosylated flavonoids were screened against the Mtb cytochrome-P450 enzyme 121 (CYP121), which is established as an approved drug target for the treatment of Mtb infection. A total of 148 glycosylated flavonoids were screened using structure-based virtual screening against the crystallized ligand, i.e., the L44 inhibitor, binding pocket in the Mtb CYP121 protein. Following this, only the top six compounds with the highest binding scores (kcal/mol) were considered for further intermolecular interaction and dynamic stability using 100 ns classical molecular dynamics simulation. These results suggested a considerable number of hydrogen and hydrophobic interactions and thermodynamic stability in comparison to the reference complex, i.e., the CYP121-L44 inhibitor. Furthermore, binding free energy via the MMGBSA method conducted on the last 10 ns interval of MD simulation trajectories revealed the substantial affinity of glycosylated compounds with Mtb CYP121 protein against reference complex. Notably, both the docked poses and residual energy decomposition via the MMGBSA method demonstrated the essential role of active residues in the interactions with glycosylated compounds by comparison with the reference complex. Collectively, this study demonstrates the viability of these screened glycosylated flavonoids as potential inhibitors of Mtb CYP121 for further experimental validation to develop a therapy for the treatment of drug-resistant Mtb strains.https://www.mdpi.com/2218-273X/12/10/1356CYP121<i>Mycobacterium tuberculosis</i>protein-ligand interactiondockingmolecular dynamic simulation |
| spellingShingle | Leena Hussein Bajrai Aiah M. Khateb Maha M. Alawi Hashim R. Felemban Anees A. Sindi Vivek Dhar Dwivedi Esam Ibraheem Azhar Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> Biomolecules CYP121 <i>Mycobacterium tuberculosis</i> protein-ligand interaction docking molecular dynamic simulation |
| title | Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> |
| title_full | Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> |
| title_fullStr | Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> |
| title_full_unstemmed | Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> |
| title_short | Glycosylated Flavonoid Compounds as Potent CYP121 Inhibitors of <i>Mycobacterium tuberculosis</i> |
| title_sort | glycosylated flavonoid compounds as potent cyp121 inhibitors of i mycobacterium tuberculosis i |
| topic | CYP121 <i>Mycobacterium tuberculosis</i> protein-ligand interaction docking molecular dynamic simulation |
| url | https://www.mdpi.com/2218-273X/12/10/1356 |
| work_keys_str_mv | AT leenahusseinbajrai glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT aiahmkhateb glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT mahamalawi glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT hashimrfelemban glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT aneesasindi glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT vivekdhardwivedi glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi AT esamibraheemazhar glycosylatedflavonoidcompoundsaspotentcyp121inhibitorsofimycobacteriumtuberculosisi |