Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme

Abstract While designing the anti-inflammatory agents targeting cyclooxygenase-2 (COX-2), we first identified a water loop around the heme playing critical role in the enzyme catalysis. The results of molecular dynamic studies supported by the strong hydrogen-bonding equilibria of the participating...

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Autores principales:	Manpreet Kaur, Baljit Kaur, Jagroop Kaur, Anudeep Kaur, Rajbir Bhatti, Palwinder Singh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/741d255a0b0a40c2b88d2e739a8db794
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spelling	oai:doaj.org-article:741d255a0b0a40c2b88d2e739a8db7942021-12-02T18:18:50ZRole of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme10.1038/s41598-020-67655-62045-2322https://doaj.org/article/741d255a0b0a40c2b88d2e739a8db7942020-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-67655-6https://doaj.org/toc/2045-2322Abstract While designing the anti-inflammatory agents targeting cyclooxygenase-2 (COX-2), we first identified a water loop around the heme playing critical role in the enzyme catalysis. The results of molecular dynamic studies supported by the strong hydrogen-bonding equilibria of the participating atoms, radical stabilization energies, the pKa of the H-donor/acceptor sites and the cyclooxygenase activity of pertinent muCOX-2 ravelled the working of the water–peptide channel for coordinating the flow of H·/electron between the heme and Y385. Based on the working of H·/electron transfer channel between the 12.5 Å distant radical generation and the radical disposal sites, a series of molecules was designed and synthesized. Among this category of compounds, an appreciably potent anti-inflammatory agent exhibiting IC50 0.06 μM against COX-2 and reversing the formalin induced analgesia and carageenan induced inflammation in mice by 90% was identified. Further it was revealed that, justifying its bidentate design, the compound targets water loop (heme bound site) and the arachidonic acid binding pockets of COX-2.Manpreet KaurBaljit KaurJagroop KaurAnudeep KaurRajbir BhattiPalwinder SinghNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Manpreet Kaur Baljit Kaur Jagroop Kaur Anudeep Kaur Rajbir Bhatti Palwinder Singh Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
description	Abstract While designing the anti-inflammatory agents targeting cyclooxygenase-2 (COX-2), we first identified a water loop around the heme playing critical role in the enzyme catalysis. The results of molecular dynamic studies supported by the strong hydrogen-bonding equilibria of the participating atoms, radical stabilization energies, the pKa of the H-donor/acceptor sites and the cyclooxygenase activity of pertinent muCOX-2 ravelled the working of the water–peptide channel for coordinating the flow of H·/electron between the heme and Y385. Based on the working of H·/electron transfer channel between the 12.5 Å distant radical generation and the radical disposal sites, a series of molecules was designed and synthesized. Among this category of compounds, an appreciably potent anti-inflammatory agent exhibiting IC50 0.06 μM against COX-2 and reversing the formalin induced analgesia and carageenan induced inflammation in mice by 90% was identified. Further it was revealed that, justifying its bidentate design, the compound targets water loop (heme bound site) and the arachidonic acid binding pockets of COX-2.
format	article
author	Manpreet Kaur Baljit Kaur Jagroop Kaur Anudeep Kaur Rajbir Bhatti Palwinder Singh
author_facet	Manpreet Kaur Baljit Kaur Jagroop Kaur Anudeep Kaur Rajbir Bhatti Palwinder Singh
author_sort	Manpreet Kaur
title	Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
title_short	Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
title_full	Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
title_fullStr	Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
title_full_unstemmed	Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
title_sort	role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/741d255a0b0a40c2b88d2e739a8db794
work_keys_str_mv	AT manpreetkaur roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme AT baljitkaur roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme AT jagroopkaur roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme AT anudeepkaur roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme AT rajbirbhatti roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme AT palwindersingh roleofwaterincyclooxygenasecatalysisanddesignofantiinflammatoryagentstargetingtwositesoftheenzyme
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Role of water in cyclooxygenase catalysis and design of anti-inflammatory agents targeting two sites of the enzyme

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