{"title":"木质素与糖原合成酶激酶-3β结合的分子对接研究","authors":"Christian Bailly , Gérard Vergoten","doi":"10.1016/j.dcmed.2022.03.002","DOIUrl":null,"url":null,"abstract":"<div><h3>Objective</h3><p>The mangrove tree <em>Xylocarpus granatum</em> J. Koenig (<em>X. granatum</em>) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-<em>δ</em>-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3<em>β</em> (GSK-3<em>β</em>), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers.</p></div><div><h3>Methods</h3><p>We investigated the binding of the 18 xylogranatins to GSK-3<em>β</em> using molecular docking in comparison with two known reference GSK-3<em>β</em> ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3<em>β</em>, the empirical energy of interaction (<em>Δ</em>E) was calculated and compared to that obtained with known GSK-3<em>β</em> inhibitors and limonoid triterpenes that target this enzyme.</p></div><div><h3>Results</h3><p>Five compounds were identified as potential GSK-3<em>β</em> binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical <em>Δ</em>E was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3<em>β</em> positions the furyl-<em>δ</em>-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3<em>β</em> binding. Structure-binding relationships are discussed.</p></div><div><h3>Conclusion</h3><p>GSK-3<em>β</em> may contribute to the anticancer effects of <em>X. granatum</em> extract. This study paves the way for the identification of other furyl-<em>δ</em>-lactone-containing limonoids as GSK-3<em>β</em> modulators.</p></div>","PeriodicalId":33578,"journal":{"name":"Digital Chinese Medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2589377722000106/pdfft?md5=c8196aff3d141d8cfdf8e55d3796d8b0&pid=1-s2.0-S2589377722000106-main.pdf","citationCount":"2","resultStr":"{\"title\":\"Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β\",\"authors\":\"Christian Bailly , Gérard Vergoten\",\"doi\":\"10.1016/j.dcmed.2022.03.002\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objective</h3><p>The mangrove tree <em>Xylocarpus granatum</em> J. Koenig (<em>X. granatum</em>) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-<em>δ</em>-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3<em>β</em> (GSK-3<em>β</em>), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers.</p></div><div><h3>Methods</h3><p>We investigated the binding of the 18 xylogranatins to GSK-3<em>β</em> using molecular docking in comparison with two known reference GSK-3<em>β</em> ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3<em>β</em>, the empirical energy of interaction (<em>Δ</em>E) was calculated and compared to that obtained with known GSK-3<em>β</em> inhibitors and limonoid triterpenes that target this enzyme.</p></div><div><h3>Results</h3><p>Five compounds were identified as potential GSK-3<em>β</em> binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical <em>Δ</em>E was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3<em>β</em> positions the furyl-<em>δ</em>-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3<em>β</em> binding. Structure-binding relationships are discussed.</p></div><div><h3>Conclusion</h3><p>GSK-3<em>β</em> may contribute to the anticancer effects of <em>X. granatum</em> extract. This study paves the way for the identification of other furyl-<em>δ</em>-lactone-containing limonoids as GSK-3<em>β</em> modulators.</p></div>\",\"PeriodicalId\":33578,\"journal\":{\"name\":\"Digital Chinese Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2022-03-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2589377722000106/pdfft?md5=c8196aff3d141d8cfdf8e55d3796d8b0&pid=1-s2.0-S2589377722000106-main.pdf\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Digital Chinese Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2589377722000106\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Digital Chinese Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2589377722000106","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
Molecular docking study of xylogranatins binding to glycogen synthase kinase-3β
Objective
The mangrove tree Xylocarpus granatum J. Koenig (X. granatum) is a medicinal plant used to treat various diseases in several Asian countries. Many bioactive natural products have been isolated from the plants, particularly several groups of limonoids, including 18 xylogranatins (Xyl-A to R), all of which bear a furyl-δ-lactone core commonly found in limonoids. Based on a structural analogy with the limonoids obacunone and gedunin, we hypothesized that xylogranatins could target the enzyme glycogen synthase kinase-3β (GSK-3β), a major target for the treatment of neurodegenerative pathologies, viral infections, and cancers.
Methods
We investigated the binding of the 18 xylogranatins to GSK-3β using molecular docking in comparison with two known reference GSK-3β ATP-competitive inhibitors, LY2090314 and AR-A014418. For each compound bound to GSK-3β, the empirical energy of interaction (ΔE) was calculated and compared to that obtained with known GSK-3β inhibitors and limonoid triterpenes that target this enzyme.
Results
Five compounds were identified as potential GSK-3β binders, Xyl-A, –C, -J, –N, and –O, for which the calculated empirical ΔE was equivalent to that calculated using the best reference molecule AR-A014418. The best ligand is Xyl-C, which is known to have marked anticancer properties. Binding of Xyl-C to the ATP-binding pocket of GSK-3β positions the furyl-δ-lactone unit deep into the binding-site cavity. Other xylogranatin derivatives bearing a central pyridine ring or a compact polycyclic structure are much less adapted for GSK-3β binding. Structure-binding relationships are discussed.
Conclusion
GSK-3β may contribute to the anticancer effects of X. granatum extract. This study paves the way for the identification of other furyl-δ-lactone-containing limonoids as GSK-3β modulators.