An In Silico Study on Withania somnifera Bioactives and Curcumin Analogs as Potential Inducers of Smoothened (Smo) Receptor of Sonic Hedgehog (SHH) Pathway to Promote Oligodendrogenesis.

IF 4.6 2区 医学 Q1 NEUROSCIENCES Molecular Neurobiology Pub Date : 2025-03-01 Epub Date: 2024-09-21 DOI:10.1007/s12035-024-04489-7
Shrey Dwivedi, Shristi Modanwal, Sneha Ranjan, Ashutosh Mishra, Nidhi Mishra, Sangeeta Singh
{"title":"An In Silico Study on Withania somnifera Bioactives and Curcumin Analogs as Potential Inducers of Smoothened (Smo) Receptor of Sonic Hedgehog (SHH) Pathway to Promote Oligodendrogenesis.","authors":"Shrey Dwivedi, Shristi Modanwal, Sneha Ranjan, Ashutosh Mishra, Nidhi Mishra, Sangeeta Singh","doi":"10.1007/s12035-024-04489-7","DOIUrl":null,"url":null,"abstract":"<p><p>Demyelinating disorder is a subset of neurodegenerative conditions wherein factors such as aging and/or auto-immune attack cause damage and degradation of myelin sheath which enwraps the neuronal axons. Lowered axonal integrity and sub-par conduction of nerve impulses due to impaired action potentials make neurodegeneration imminent as the neurons do not have mitotic ability to replenish their numbers. Oligodendrocytes (OLs) myelinate the axonal segments of neurons and perform neuronal maintenance. Neuroregenerative stem cell therapy exploits this property for remyelination by targeting OL replenishment using in vitro stem cell differentiation protocols for inducing OL lineage cells. But some shortcomings of such protocols are over-reliance on synthetic inducers, lengthy differentiation process, low differentiation efficiency besides being financially expensive. This in silico study sought to identify herbal substitutes of currently available OL-lineage-specific synthetic inducers from a virtual library of curcumin analogs and Withania somnifera bioactives. Smoothened (Smo) receptor belonging to the canonical sonic hedgehog (SHH) signaling pathway promotes in vivo differentiation of OLs as well as their subsequent lineage progression to myelinating OLs. Therefore, we performed pharmacokinetics prediction for the bioactives followed by their molecular docking and molecular dynamics simulation with Smo. From a pool of 1289 curcumin analogs and 80 Withania somnifera-derived bioactives, the best docked ligands were identified as the compounds with PubChem IDs 68815167 and 25880, respectively. Molecular dynamics simulation of these ligands further concluded the Withania somnifera bioactive 25880 to have the best activity with Smo. This compound may be deemed as a potential lead molecule for an agonistic interaction with and activation of Smo to initialize its downstream signaling cascade for enriching OL differentiation.</p>","PeriodicalId":18762,"journal":{"name":"Molecular Neurobiology","volume":" ","pages":"3523-3543"},"PeriodicalIF":4.6000,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12035-024-04489-7","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Demyelinating disorder is a subset of neurodegenerative conditions wherein factors such as aging and/or auto-immune attack cause damage and degradation of myelin sheath which enwraps the neuronal axons. Lowered axonal integrity and sub-par conduction of nerve impulses due to impaired action potentials make neurodegeneration imminent as the neurons do not have mitotic ability to replenish their numbers. Oligodendrocytes (OLs) myelinate the axonal segments of neurons and perform neuronal maintenance. Neuroregenerative stem cell therapy exploits this property for remyelination by targeting OL replenishment using in vitro stem cell differentiation protocols for inducing OL lineage cells. But some shortcomings of such protocols are over-reliance on synthetic inducers, lengthy differentiation process, low differentiation efficiency besides being financially expensive. This in silico study sought to identify herbal substitutes of currently available OL-lineage-specific synthetic inducers from a virtual library of curcumin analogs and Withania somnifera bioactives. Smoothened (Smo) receptor belonging to the canonical sonic hedgehog (SHH) signaling pathway promotes in vivo differentiation of OLs as well as their subsequent lineage progression to myelinating OLs. Therefore, we performed pharmacokinetics prediction for the bioactives followed by their molecular docking and molecular dynamics simulation with Smo. From a pool of 1289 curcumin analogs and 80 Withania somnifera-derived bioactives, the best docked ligands were identified as the compounds with PubChem IDs 68815167 and 25880, respectively. Molecular dynamics simulation of these ligands further concluded the Withania somnifera bioactive 25880 to have the best activity with Smo. This compound may be deemed as a potential lead molecule for an agonistic interaction with and activation of Smo to initialize its downstream signaling cascade for enriching OL differentiation.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
关于睡茄生物活性物质和姜黄素类似物作为音速刺猬素 (SHH) 通路的 Smoothened (Smo) 受体潜在诱导剂以促进少突胶质细胞生成的硅学研究
脱髓鞘疾病是神经退行性疾病的一个分支,在这种疾病中,衰老和/或自身免疫攻击等因素会导致包裹神经元轴突的髓鞘受损和降解。由于动作电位受损,轴突完整性降低,神经冲动传导能力减弱,神经变性迫在眉睫,因为神经元没有有丝分裂能力来补充其数量。少突胶质细胞(Oligodendrocytes,OLs)髓鞘化神经元的轴突节段,对神经元进行维护。神经再生干细胞疗法利用这一特性,通过体外干细胞分化方案诱导OL系细胞,针对OL补充进行再髓鞘化。但这类方案的一些缺点是过度依赖合成诱导剂、分化过程漫长、分化效率低,而且经济上也很昂贵。本默克研究试图从姜黄素类似物和睡莲生物活性物质的虚拟库中找出目前可用的 OL 系特异性合成诱导剂的草药替代品。属于典型声刺猬(SHH)信号通路的Smoothened(Smo)受体能促进体内OLs的分化及其随后向髓化OLs的系谱进展。因此,我们对生物活性物质进行了药代动力学预测,然后与 Smo 进行了分子对接和分子动力学模拟。从 1289 种姜黄素类似物和 80 种从睡茄提取的生物活性物质中,我们确定了最佳对接配体,它们分别是 PubChem ID 为 68815167 和 25880 的化合物。对这些配体进行分子动力学模拟后,进一步得出结论,在与 Smo 的相互作用中,薇甘菊生物活性物质 25880 的活性最佳。该化合物可被视为一种潜在的先导分子,可与 Smo 发生激动作用并激活 Smo,从而启动其下游信号级联,促进 OL 的分化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Molecular Neurobiology
Molecular Neurobiology 医学-神经科学
CiteScore
9.00
自引率
2.00%
发文量
480
审稿时长
1 months
期刊介绍: Molecular Neurobiology is an exciting journal for neuroscientists needing to stay in close touch with progress at the forefront of molecular brain research today. It is an especially important periodical for graduate students and "postdocs," specifically designed to synthesize and critically assess research trends for all neuroscientists hoping to stay active at the cutting edge of this dramatically developing area. This journal has proven to be crucial in departmental libraries, serving as essential reading for every committed neuroscientist who is striving to keep abreast of all rapid developments in a forefront field. Most recent significant advances in experimental and clinical neuroscience have been occurring at the molecular level. Until now, there has been no journal devoted to looking closely at this fragmented literature in a critical, coherent fashion. Each submission is thoroughly analyzed by scientists and clinicians internationally renowned for their special competence in the areas treated.
期刊最新文献
Correction: Human Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Attenuate Blood-Spinal Cord Barrier Disruption via the TIMP2/MMP Pathway After Acute Spinal Cord Injury. Correction to: PRDX6 Inhibits Neurogenesis through Downregulation of WDFY1-Mediated TLR4 Signal. Correction to: SIRT6 Improves Hippocampal Neurogenesis Following Prolonged Sleep Deprivation Through Modulating Energy Metabolism in Developing rats. Correction: Inhibition of microRNA-155 Protects Retinal Function Through Attenuation of Inflammation in Retinal Degeneration. Correction: Vilazodone, a Novel SSRI Antidepressant with 5-HT1A Partial Agonist Properties: Diminished Potentiation of Chronic Oral Methylphenidate-Induced Dynorphin Expression in the Striatum in Adolescent Male Rats.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1