Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA
The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier Ltd
2019
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| Online Access: | http://umpir.ump.edu.my/id/eprint/25636/ http://umpir.ump.edu.my/id/eprint/25636/1/Design%20and%20synthesis%20of%20a%20novel%20mPGES-1%20lead%20inhibitor%20.pdf |
| _version_ | 1848822330082459648 |
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| author | Mohd F. F., Mohd Aluwi Rullah, Kamal Koeberle, Andreas Werz, Oliver Nur Sakinah, Abdul Razak Wei, Leong Sze Fatimah, Salim Nor Hadiani, Ismail Ibrahim, Jantan Wai, Lam K. |
| author_facet | Mohd F. F., Mohd Aluwi Rullah, Kamal Koeberle, Andreas Werz, Oliver Nur Sakinah, Abdul Razak Wei, Leong Sze Fatimah, Salim Nor Hadiani, Ismail Ibrahim, Jantan Wai, Lam K. |
| author_sort | Mohd F. F., Mohd Aluwi |
| building | UMP Institutional Repository |
| collection | Online Access |
| description | The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors. |
| first_indexed | 2025-11-15T02:39:31Z |
| format | Article |
| id | ump-25636 |
| institution | Universiti Malaysia Pahang |
| institution_category | Local University |
| language | English |
| last_indexed | 2025-11-15T02:39:31Z |
| publishDate | 2019 |
| publisher | Elsevier Ltd |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | ump-256362019-11-21T01:53:48Z http://umpir.ump.edu.my/id/eprint/25636/ Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA Mohd F. F., Mohd Aluwi Rullah, Kamal Koeberle, Andreas Werz, Oliver Nur Sakinah, Abdul Razak Wei, Leong Sze Fatimah, Salim Nor Hadiani, Ismail Ibrahim, Jantan Wai, Lam K. R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors. Elsevier Ltd 2019-11-15 Article PeerReviewed pdf en http://umpir.ump.edu.my/id/eprint/25636/1/Design%20and%20synthesis%20of%20a%20novel%20mPGES-1%20lead%20inhibitor%20.pdf Mohd F. F., Mohd Aluwi and Rullah, Kamal and Koeberle, Andreas and Werz, Oliver and Nur Sakinah, Abdul Razak and Wei, Leong Sze and Fatimah, Salim and Nor Hadiani, Ismail and Ibrahim, Jantan and Wai, Lam K. (2019) Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA. Journal of Molecular Structure, 1196. pp. 844-850. ISSN 0022-2860. (Published) https://doi.org/10.1016/j.molstruc.2019.07.004 https://doi.org/10.1016/j.molstruc.2019.07.004 |
| spellingShingle | R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica Mohd F. F., Mohd Aluwi Rullah, Kamal Koeberle, Andreas Werz, Oliver Nur Sakinah, Abdul Razak Wei, Leong Sze Fatimah, Salim Nor Hadiani, Ismail Ibrahim, Jantan Wai, Lam K. Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title | Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title_full | Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title_fullStr | Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title_full_unstemmed | Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title_short | Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA |
| title_sort | design and synthesis of a novel mpges-1 lead inhibitor guided by 3d-qsar comfa |
| topic | R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica |
| url | http://umpir.ump.edu.my/id/eprint/25636/ http://umpir.ump.edu.my/id/eprint/25636/ http://umpir.ump.edu.my/id/eprint/25636/ http://umpir.ump.edu.my/id/eprint/25636/1/Design%20and%20synthesis%20of%20a%20novel%20mPGES-1%20lead%20inhibitor%20.pdf |