Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4
Fascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious ad...
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doaj-38ed3a9644284502b61ec0d2b39c223c2021-02-18T08:23:36ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462021-02-01910.3389/fchem.2021.614154614154Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4Yan Liang0Huili Quan1Tong Bu2Xuedong Li3Xingang Liu4Songsong Wang5Dian He6Qingzhong Jia7Yang Zhang8Materia Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, ChinaThe Fourth Hospital of Shijiazhuang, Shijiazhuang, ChinaDepartment of Pharmacology, Hebei Medical University, Shijiazhuang, ChinaDepartment of Pharmacology, Hebei Medical University, Shijiazhuang, ChinaDepartment of Pharmacology, Hebei Medical University, Shijiazhuang, ChinaThe Second Hospital of Hebei Medical University, Shijiazhuang, ChinaMateria Medica Development Group, Institute of Medicinal Chemistry, Lanzhou University School of Pharmacy, Lanzhou, ChinaDepartment of Pharmacology, Hebei Medical University, Shijiazhuang, ChinaDepartment of Pharmacology, Hebei Medical University, Shijiazhuang, ChinaFascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious adverse effects, 18 tetrahydro-β-carboline analogs (compounds 6a-i and 7a-i) were designed and synthesized via breaking the planarity of fascaplysin, and the biological activities of the synthesized compounds were evaluated by MTT assay and CDK4/CycD3 enzyme inhibition assay. The title compounds showed varying degrees of inhibitory activities, especially the cytotoxicity of compound 6c against HeLa cells (IC50 = 1.03 ± 0.19 μM) with quite weak cytotoxicity toward the normal cells WI-38 (IC50 = 311.51 ± 56.06 μM), and the kinase inhibition test indicated that compound 6c was a potential CDK4 inhibitor. In order to further compare the action mechanisms of planar and nonplanar molecules on CDK4, the studied complexes of CDK4 bound with fascaplysin and three representative compounds (compound 6a-c) with bioactivities gradient were constructed by molecular docking and further verified through molecular dynamic simulation, which identified the key residues contributing to the ligands’ binding. By comparing the binding modes of the constructed systems, it could be found that the residues contributing significantly to compound 6c′s binding were highly consistent with those contributing significantly to fascaplysin’s binding. Through the design, synthesis of the nonplanar fascaplysin derivatives, and binding mechanism analysis, some valuable hints for the discovery of antitumor drug candidates could be provided.https://www.frontiersin.org/articles/10.3389/fchem.2021.614154/fullfascaplysinnonplanarMTT assaymolecular dockingMD simulation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yan Liang Huili Quan Tong Bu Xuedong Li Xingang Liu Songsong Wang Dian He Qingzhong Jia Yang Zhang |
spellingShingle |
Yan Liang Huili Quan Tong Bu Xuedong Li Xingang Liu Songsong Wang Dian He Qingzhong Jia Yang Zhang Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 Frontiers in Chemistry fascaplysin nonplanar MTT assay molecular docking MD simulation |
author_facet |
Yan Liang Huili Quan Tong Bu Xuedong Li Xingang Liu Songsong Wang Dian He Qingzhong Jia Yang Zhang |
author_sort |
Yan Liang |
title |
Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 |
title_short |
Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 |
title_full |
Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 |
title_fullStr |
Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 |
title_full_unstemmed |
Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4 |
title_sort |
comparison of the inhibitory binding modes between the planar fascaplysin and its nonplanar tetrahydro-β-carboline analogs in cdk4 |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Chemistry |
issn |
2296-2646 |
publishDate |
2021-02-01 |
description |
Fascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious adverse effects, 18 tetrahydro-β-carboline analogs (compounds 6a-i and 7a-i) were designed and synthesized via breaking the planarity of fascaplysin, and the biological activities of the synthesized compounds were evaluated by MTT assay and CDK4/CycD3 enzyme inhibition assay. The title compounds showed varying degrees of inhibitory activities, especially the cytotoxicity of compound 6c against HeLa cells (IC50 = 1.03 ± 0.19 μM) with quite weak cytotoxicity toward the normal cells WI-38 (IC50 = 311.51 ± 56.06 μM), and the kinase inhibition test indicated that compound 6c was a potential CDK4 inhibitor. In order to further compare the action mechanisms of planar and nonplanar molecules on CDK4, the studied complexes of CDK4 bound with fascaplysin and three representative compounds (compound 6a-c) with bioactivities gradient were constructed by molecular docking and further verified through molecular dynamic simulation, which identified the key residues contributing to the ligands’ binding. By comparing the binding modes of the constructed systems, it could be found that the residues contributing significantly to compound 6c′s binding were highly consistent with those contributing significantly to fascaplysin’s binding. Through the design, synthesis of the nonplanar fascaplysin derivatives, and binding mechanism analysis, some valuable hints for the discovery of antitumor drug candidates could be provided. |
topic |
fascaplysin nonplanar MTT assay molecular docking MD simulation |
url |
https://www.frontiersin.org/articles/10.3389/fchem.2021.614154/full |
work_keys_str_mv |
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