Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk <i>Dicathais orbita</i> (<i>D. orbita</i>) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and...

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Autores principales:	Md. Mominur Rahman, Md. Junaid, S. M. Zahid Hosen, Mohammad Mostafa, Lei Liu, Kirsten Benkendorff
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Dicathais orbita</i> inflammation COX-1/2 molecular docking molecular dynamics drug-likeness Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/bdb23c99f66342c795c5dd71e575be79
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spelling	oai:doaj.org-article:bdb23c99f66342c795c5dd71e575be792021-11-11T18:31:32ZMollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition10.3390/molecules262165381420-3049https://doaj.org/article/bdb23c99f66342c795c5dd71e575be792021-10-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6538https://doaj.org/toc/1420-3049Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk <i>Dicathais orbita</i> (<i>D. orbita</i>) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human <i>ether-a-go–go gene (hERG) I</i> inhibitors, and the oral acute toxicity LD<sub>50</sub> in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.Md. Mominur RahmanMd. JunaidS. M. Zahid HosenMohammad MostafaLei LiuKirsten BenkendorffMDPI AGarticle<i>Dicathais orbita</i>inflammationCOX-1/2molecular dockingmolecular dynamicsdrug-likenessOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6538, p 6538 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Dicathais orbita</i> inflammation COX-1/2 molecular docking molecular dynamics drug-likeness Organic chemistry QD241-441
spellingShingle	<i>Dicathais orbita</i> inflammation COX-1/2 molecular docking molecular dynamics drug-likeness Organic chemistry QD241-441 Md. Mominur Rahman Md. Junaid S. M. Zahid Hosen Mohammad Mostafa Lei Liu Kirsten Benkendorff Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
description	Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk <i>Dicathais orbita</i> (<i>D. orbita</i>) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human <i>ether-a-go–go gene (hERG) I</i> inhibitors, and the oral acute toxicity LD<sub>50</sub> in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.
format	article
author	Md. Mominur Rahman Md. Junaid S. M. Zahid Hosen Mohammad Mostafa Lei Liu Kirsten Benkendorff
author_facet	Md. Mominur Rahman Md. Junaid S. M. Zahid Hosen Mohammad Mostafa Lei Liu Kirsten Benkendorff
author_sort	Md. Mominur Rahman
title	Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
title_short	Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
title_full	Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
title_fullStr	Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
title_full_unstemmed	Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
title_sort	mollusc-derived brominated indoles for the selective inhibition of cyclooxygenase: a computational expedition
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/bdb23c99f66342c795c5dd71e575be79
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Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

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