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Published (Version of record)CC BY V4.0, Open Access
Published (Version of record)CC BY V4.0, Open
Journal article
Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
Molecules, Vol.26(21), pp.1-27
29/10/2021
PMCID: PMC8587571
PMID: 34770946
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Source: InCites
Abstract
Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) 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 ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 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.
Details
- Title
- Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition
- Creators
- Md. Mominur Rahman - Southern Cross UniversityMd Junaid - Bangladesh Council of Scientific and Industrial ResearchS. M. Zahid Hosen - Bangladesh Council of Scientific and Industrial ResearchMohammad Mostafa - Bangladesh Council of Scientific and Industrial ResearchLei Liu - Southern Cross UniversityKirsten Benkendorff - Southern Cross University
- Publication Details
- Molecules, Vol.26(21), pp.1-27
- Publisher
- MDPI AG
- Grant note
- Marine Ecology Research Centre, Southern Cross University, and an Australian Government research training postgraduate (RTP) scholarship from Southern Cross University for M.M.R.
- Identifiers
- 991012978266802368
- Copyright
- © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
- Academic Unit
- Marine Ecology Research Centre; Faculty of Science and Engineering; Science; School of Environment, Science and Engineering; Southern Cross Plant Science; National Marine Science Centre
- Language
- English
- Resource Type
- Journal article