Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors
Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials...
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Elsevier
2023-02-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S240584402300676X |
| _version_ | 1811161769647800320 |
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| author | E. Varun K. Bhakti K. Aishwarya R Hosur Suraj M.R. Jagadish P. Mohana Kumara |
| author_facet | E. Varun K. Bhakti K. Aishwarya R Hosur Suraj M.R. Jagadish P. Mohana Kumara |
| author_sort | E. Varun |
| collection | DOAJ |
| description | Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials against a wide range of cancers. Flavopiridol was recently approved as an orphan drug for chronic lymphocytic leukemia treatment. In this study, we report the isolation and characterization of rohitukine from the bark of D. binectariferum. Further, rohitukine was estimated across the Western-Ghats and the North-East regions of India. Additionally, D. binectariferum is also reported (∼45 compounds) to produce many natural derivatives of rohitukine and terpenoids, which were investigated in-silico to reveal promising CDK inhibitors. The metabolite fingerprinting of tissues of D. binectariferum was studied using HPTLC and FTIR. The distribution of major chromone alkaloid rohitukine was estimated by HPLC. Further, the pharmacological potential of D. binectariferum compounds was evaluated in-silico by discovering the potential protein targets, molecular docking, ADMET analysis and MD simulation. The isolation of rohitukine has yielded 0.6% from the bark of D. binectariferum. A higher percent of rohitukine was found in the Jog populations (0.58% & 1.28%: leaf & bark), whereas least was observed in the Phasighat population (∼0.06%: both leaf & bark). Across the geographic regions, a higher percent of rohitukine was found in the Central-southern Western Ghats, whereas lower in the northern parts of the Western Ghats and Northeast regions. The leaves produce a considerably higher percent of rohitukine and could be used as a sustainable source of rohitukine. The rohitukine analogues, along with other chromone alkaloids of D. binecatariferum were found to be more interactive with the “kinases” family of proteins, majorly “Serine/threonine-protein kinase PFTAIRE-2” (CDK15) with high confidence level (0.94–0.98). The molecular docking of these chromone alkaloids found a strong binding energy with six CDKs (−3.1 to −10.6 kcal/mol) along with a promising ADMET profile. In addition, molecular dynamic simulation found that the rohitukine complexes are virtually constant with CDK-1, 2, 9 and 15, which is substantiated with MM-PBSA free energy calculations. The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs. |
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| spelling | doaj.art-79da07a713a942df92f022823bb36ecc2023-03-02T05:01:42ZengElsevierHeliyon2405-84402023-02-0192e13469Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitorsE. Varun0K. Bhakti1K. Aishwarya2R Hosur Suraj3M.R. Jagadish4P. Mohana Kumara5Center for Ayurveda Biology and Holistic Nutrition, The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, 560064, IndiaCenter for Ayurveda Biology and Holistic Nutrition, The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, 560064, IndiaCenter for Ayurveda Biology and Holistic Nutrition, The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, 560064, IndiaCollege of Forestry, Sirsi, 581401, University of Agricultural Sciences, Dharwad, IndiaCollege of Forestry, Sirsi, 581401, University of Agricultural Sciences, Dharwad, IndiaCenter for Ayurveda Biology and Holistic Nutrition, The University of Trans-Disciplinary Health Sciences and Technology (TDU), Bengaluru, 560064, India; Department of Biotechnology and Crop improvement, Kittur Rani Channamma College of Horticulture (KRCCH), Arabhavi, 591218, University of Horticultural Sciences, Bagalkot, India; Corresponding author. Department of Biotechnology and Crop improvement, Kittur Rani Channamma College of Horticulture (KRCCH), Arabhavi, 591218, University of Horticultural Sciences, Bagalkot, India. Tel./fax: 08332 22070.Dysoxylum binectariferum is an important medicinal plant distributed in the Western Ghats of India. The species has gained international importance for its anticancer component, rohitukine, a chromone alkaloid. Flavopiridol, P-276-00 and IIIM-290 are the derivatives of rohitukine in clinical trials against a wide range of cancers. Flavopiridol was recently approved as an orphan drug for chronic lymphocytic leukemia treatment. In this study, we report the isolation and characterization of rohitukine from the bark of D. binectariferum. Further, rohitukine was estimated across the Western-Ghats and the North-East regions of India. Additionally, D. binectariferum is also reported (∼45 compounds) to produce many natural derivatives of rohitukine and terpenoids, which were investigated in-silico to reveal promising CDK inhibitors. The metabolite fingerprinting of tissues of D. binectariferum was studied using HPTLC and FTIR. The distribution of major chromone alkaloid rohitukine was estimated by HPLC. Further, the pharmacological potential of D. binectariferum compounds was evaluated in-silico by discovering the potential protein targets, molecular docking, ADMET analysis and MD simulation. The isolation of rohitukine has yielded 0.6% from the bark of D. binectariferum. A higher percent of rohitukine was found in the Jog populations (0.58% & 1.28%: leaf & bark), whereas least was observed in the Phasighat population (∼0.06%: both leaf & bark). Across the geographic regions, a higher percent of rohitukine was found in the Central-southern Western Ghats, whereas lower in the northern parts of the Western Ghats and Northeast regions. The leaves produce a considerably higher percent of rohitukine and could be used as a sustainable source of rohitukine. The rohitukine analogues, along with other chromone alkaloids of D. binecatariferum were found to be more interactive with the “kinases” family of proteins, majorly “Serine/threonine-protein kinase PFTAIRE-2” (CDK15) with high confidence level (0.94–0.98). The molecular docking of these chromone alkaloids found a strong binding energy with six CDKs (−3.1 to −10.6 kcal/mol) along with a promising ADMET profile. In addition, molecular dynamic simulation found that the rohitukine complexes are virtually constant with CDK-1, 2, 9 and 15, which is substantiated with MM-PBSA free energy calculations. The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.http://www.sciencedirect.com/science/article/pii/S240584402300676XDysoxylum binectariferumRohitukineHPLCPharmacokinetic potentialCDKs |
| spellingShingle | E. Varun K. Bhakti K. Aishwarya R Hosur Suraj M.R. Jagadish P. Mohana Kumara Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors Heliyon Dysoxylum binectariferum Rohitukine HPLC Pharmacokinetic potential CDKs |
| title | Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors |
| title_full | Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors |
| title_fullStr | Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors |
| title_full_unstemmed | Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors |
| title_short | Rohitukine content across the geographical distribution of Dysoxylum binectariferum Hook F. and its natural derivatives as potential sources of CDK inhibitors |
| title_sort | rohitukine content across the geographical distribution of dysoxylum binectariferum hook f and its natural derivatives as potential sources of cdk inhibitors |
| topic | Dysoxylum binectariferum Rohitukine HPLC Pharmacokinetic potential CDKs |
| url | http://www.sciencedirect.com/science/article/pii/S240584402300676X |
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