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...

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Main Authors:	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.
Format:	Article
Language:	English
Published:	Elsevier Ltd 2019
Subjects:	R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica
Online Access:	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

id	ump-25636
recordtype	eprints
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 https://doi.org/10.1016/j.molstruc.2019.07.004 https://doi.org/10.1016/j.molstruc.2019.07.004
repository_type	Digital Repository
institution_category	Local University
institution	Universiti Malaysia Pahang
building	UMP Institutional Repository
collection	Online Access
language	English
topic	R Medicine (General) RM Therapeutics. Pharmacology RS Pharmacy and materia medica
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
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.
format	Article
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
title	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_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_sort	design and synthesis of a novel mpges-1 lead inhibitor guided by 3d-qsar comfa
publisher	Elsevier Ltd
publishDate	2019
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
first_indexed	2023-09-18T22:39:29Z
last_indexed	2023-09-18T22:39:29Z
_version_	1777416818282987520

Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

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