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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MDPI AG
2021-10-01
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T05:56:08Z |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:56:08Z |
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| spelling | doaj.art-bdb23c99f66342c795c5dd71e575be792023-11-22T21:22:49ZengMDPI AGMolecules1420-30492021-10-012621653810.3390/molecules26216538Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational ExpeditionMd. Mominur Rahman0Md. Junaid1S. M. Zahid Hosen2Mohammad Mostafa3Lei Liu4Kirsten Benkendorff5Marine Ecology Research Centre, Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, AustraliaMolecular Modeling Drug-design and Discovery Laboratory, Pharmacology Research Division, BCSIR Laboratories Chattogram, Bangladesh Council of Scientific and Industrial Research, Chattogram 4217, BangladeshMolecular Modeling Drug-design and Discovery Laboratory, Pharmacology Research Division, BCSIR Laboratories Chattogram, Bangladesh Council of Scientific and Industrial Research, Chattogram 4217, BangladeshMolecular Modeling Drug-design and Discovery Laboratory, Pharmacology Research Division, BCSIR Laboratories Chattogram, Bangladesh Council of Scientific and Industrial Research, Chattogram 4217, BangladeshSouthern Cross Plant Science, Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, AustraliaMarine Ecology Research Centre, Faculty of Science and Engineering, Southern Cross University, Lismore, NSW 2480, AustraliaInflammation 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.https://www.mdpi.com/1420-3049/26/21/6538<i>Dicathais orbita</i>inflammationCOX-1/2molecular dockingmolecular dynamicsdrug-likeness |
| spellingShingle | 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 Molecules <i>Dicathais orbita</i> inflammation COX-1/2 molecular docking molecular dynamics drug-likeness |
| title | 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_short | 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 |
| topic | <i>Dicathais orbita</i> inflammation COX-1/2 molecular docking molecular dynamics drug-likeness |
| url | https://www.mdpi.com/1420-3049/26/21/6538 |
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