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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 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 ?M 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.

SUBMITTER: Kaur M 

PROVIDER: S-EPMC7329864 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Kaur Manpreet M   Kaur Baljit B   Kaur Jagroop J   Kaur Anudeep A   Bhatti Rajbir R   Singh Palwinder P  

Scientific reports 20200701 1


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 pK<sub>a</sub> of the H-donor/acceptor sites and the cyclooxygenase activity of pertinent muCOX-2 ravelled the working of the water-peptide channel for coordinating t  ...[more]

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