Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors
In this report, a structurally unique phenothiazine (PTZ) core is linked with glutamic acid-based dendrons through a solid-phase peptide synthesis approach to access a variety of PTZ-linked dendrons conveniently. Inferior cytotoxicity of anionic surface-linked second-generation glutamic acid-based d...
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The Royal Society
2025-04-01
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| Series: | Royal Society Open Science |
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| Online Access: | https://royalsocietypublishing.org/doi/10.1098/rsos.241628 |
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| author | Sameer Singh Aditi Gangopadhyay Sriram D Manab Chakravarty |
| author_facet | Sameer Singh Aditi Gangopadhyay Sriram D Manab Chakravarty |
| author_sort | Sameer Singh |
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| description | In this report, a structurally unique phenothiazine (PTZ) core is linked with glutamic acid-based dendrons through a solid-phase peptide synthesis approach to access a variety of PTZ-linked dendrons conveniently. Inferior cytotoxicity of anionic surface-linked second-generation glutamic acid-based dendrons would be more desirable for various applications than respective lysine-based dendrons. Solid-phase synthesis of PTZ-linked glutamic acid-based dendrons would be a novel approach to access this class of molecules. These newly synthesized dendrons were screened as an inhibitor against the main protease (Mpro) enzyme, proposed to be the best target against SARS-CoV-2. The preliminary assay studies designated a moderate response for the Mpro inhibition, specifically by tryptophan (Trp)-enriched dendron, among other analogues, which play a vital role in combating COVID-19. Further, the experimental studies realize the essential contribution of the PTZ core in interacting with the Mpro enzyme. Molecular dynamics (MD) simulations revealed that the active dendrons formed stable complexes with Mpro, and the binding affinity of the Trp-based PTZ-linked dendrons was higher than that of the decoy dendron analogue. |
| format | Article |
| id | doaj-art-9df4b3d58836434e94d49d42bd20d786 |
| institution | OA Journals |
| issn | 2054-5703 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | The Royal Society |
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| series | Royal Society Open Science |
| spelling | doaj-art-9df4b3d58836434e94d49d42bd20d7862025-08-20T01:51:24ZengThe Royal SocietyRoyal Society Open Science2054-57032025-04-0112410.1098/rsos.241628Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitorsSameer Singh0Aditi Gangopadhyay1Sriram D2Manab Chakravarty3Department of Chemistry, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, IndiaDepartment of Chemical Technology, University of Calcutta, Kolkata, West Bengal, IndiaDepartment of Pharmacy, Birla Institute of Technology & Science Pilani, Hyderabad, Telangana, IndiaDepartment of Chemistry, Birla Institute of Technology & Science Pilani - Hyderabad Campus, Hyderabad, Telangana, IndiaIn this report, a structurally unique phenothiazine (PTZ) core is linked with glutamic acid-based dendrons through a solid-phase peptide synthesis approach to access a variety of PTZ-linked dendrons conveniently. Inferior cytotoxicity of anionic surface-linked second-generation glutamic acid-based dendrons would be more desirable for various applications than respective lysine-based dendrons. Solid-phase synthesis of PTZ-linked glutamic acid-based dendrons would be a novel approach to access this class of molecules. These newly synthesized dendrons were screened as an inhibitor against the main protease (Mpro) enzyme, proposed to be the best target against SARS-CoV-2. The preliminary assay studies designated a moderate response for the Mpro inhibition, specifically by tryptophan (Trp)-enriched dendron, among other analogues, which play a vital role in combating COVID-19. Further, the experimental studies realize the essential contribution of the PTZ core in interacting with the Mpro enzyme. Molecular dynamics (MD) simulations revealed that the active dendrons formed stable complexes with Mpro, and the binding affinity of the Trp-based PTZ-linked dendrons was higher than that of the decoy dendron analogue.https://royalsocietypublishing.org/doi/10.1098/rsos.241628phenothiazine-linkedglutamic aciddendronsSARS-CoV2 |
| spellingShingle | Sameer Singh Aditi Gangopadhyay Sriram D Manab Chakravarty Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors Royal Society Open Science phenothiazine-linked glutamic acid dendrons SARS-CoV2 |
| title | Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors |
| title_full | Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors |
| title_fullStr | Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors |
| title_full_unstemmed | Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors |
| title_short | Phenothiazine-linked glutamic acid dendrons: an easy access and a new class of SARS-CoV-2 main protease inhibitors |
| title_sort | phenothiazine linked glutamic acid dendrons an easy access and a new class of sars cov 2 main protease inhibitors |
| topic | phenothiazine-linked glutamic acid dendrons SARS-CoV2 |
| url | https://royalsocietypublishing.org/doi/10.1098/rsos.241628 |
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