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:	Rullah, Kamal, Mohd Aluwi, Mohd Fadhlizil Fasihi, Koeberle, Andreas, Werz, Oliver, Abdul Razak, Nur Sakinah, Wei, Leong Sze, Salim, Fatimah, Ismail, Nor Hadiani, Jantan, Ibrahim, Wai, Lam Kok
Format:	Article
Language:	English English
Published:	Elsevier 2019
Subjects:	RS403 Materia Medica-Pharmaceutical Chemistry
Online Access:	http://irep.iium.edu.my/74958/ http://irep.iium.edu.my/74958/ http://irep.iium.edu.my/74958/1/Kamal%20Rullah%2021.pdf http://irep.iium.edu.my/74958/7/74958_Design%20and%20synthesis%20of%20a%20novel%20_scopus.pdf

id	iium-74958
recordtype	eprints
spelling	iium-749582019-10-26T17:35:14Z http://irep.iium.edu.my/74958/ Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA Rullah, Kamal Mohd Aluwi, Mohd Fadhlizil Fasihi Koeberle, Andreas Werz, Oliver Abdul Razak, Nur Sakinah Wei, Leong Sze Salim, Fatimah Ismail, Nor Hadiani Jantan, Ibrahim Wai, Lam Kok RS403 Materia Medica-Pharmaceutical Chemistry 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 2019-11-15 Article PeerReviewed application/pdf en http://irep.iium.edu.my/74958/1/Kamal%20Rullah%2021.pdf application/pdf en http://irep.iium.edu.my/74958/7/74958_Design%20and%20synthesis%20of%20a%20novel%20_scopus.pdf Rullah, Kamal and Mohd Aluwi, Mohd Fadhlizil Fasihi and Koeberle, Andreas and Werz, Oliver and Abdul Razak, Nur Sakinah and Wei, Leong Sze and Salim, Fatimah and Ismail, Nor Hadiani and Jantan, Ibrahim and Wai, Lam Kok (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://www.sciencedirect.com/science/article/pii/S0022286019308385#!
repository_type	Digital Repository
institution_category	Local University
institution	International Islamic University Malaysia
building	IIUM Repository
collection	Online Access
language	English English
topic	RS403 Materia Medica-Pharmaceutical Chemistry
spellingShingle	RS403 Materia Medica-Pharmaceutical Chemistry Rullah, Kamal Mohd Aluwi, Mohd Fadhlizil Fasihi Koeberle, Andreas Werz, Oliver Abdul Razak, Nur Sakinah Wei, Leong Sze Salim, Fatimah Ismail, Nor Hadiani Jantan, Ibrahim Wai, Lam Kok 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	Rullah, Kamal Mohd Aluwi, Mohd Fadhlizil Fasihi Koeberle, Andreas Werz, Oliver Abdul Razak, Nur Sakinah Wei, Leong Sze Salim, Fatimah Ismail, Nor Hadiani Jantan, Ibrahim Wai, Lam Kok
author_facet	Rullah, Kamal Mohd Aluwi, Mohd Fadhlizil Fasihi Koeberle, Andreas Werz, Oliver Abdul Razak, Nur Sakinah Wei, Leong Sze Salim, Fatimah Ismail, Nor Hadiani Jantan, Ibrahim Wai, Lam Kok
author_sort	Rullah, Kamal
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
publishDate	2019
url	http://irep.iium.edu.my/74958/ http://irep.iium.edu.my/74958/ http://irep.iium.edu.my/74958/1/Kamal%20Rullah%2021.pdf http://irep.iium.edu.my/74958/7/74958_Design%20and%20synthesis%20of%20a%20novel%20_scopus.pdf
first_indexed	2023-09-18T21:46:05Z
last_indexed	2023-09-18T21:46:05Z
_version_	1777413459228491776

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

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