Dwivedi Shrey, Modanwal Shristi, Ranjan Sneha, Mishra Ashutosh, Mishra Nidhi, Singh Sangeeta
Department of Applied Sciences, Indian Institute of Information Technology Allahabad, Devghat, Jhalwa, Prayagraj, Uttar Pradesh, 211015, India.
Mol Neurobiol. 2025 Mar;62(3):3523-3543. doi: 10.1007/s12035-024-04489-7. Epub 2024 Sep 21.
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.
脱髓鞘疾病是神经退行性疾病的一个子集，其中衰老和/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退化。由于动作电位受损，轴突完整性降低和神经冲动传导不佳，使得神经退行性变迫在眉睫，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（OLs）使神经元的轴突段髓鞘化并进行神经元维持。神经再生干细胞疗法利用这一特性，通过使用体外干细胞分化方案诱导OL谱系细胞来靶向补充OL，从而实现髓鞘再生。但此类方案存在一些缺点，如过度依赖合成诱导剂、分化过程冗长、分化效率低且成本高昂。这项计算机模拟研究旨在从姜黄素类似物和印度人参生物活性物质的虚拟库中识别当前可用的OL谱系特异性合成诱导剂的草药替代品。属于经典音猬因子（SHH）信号通路的平滑（Smo）受体促进OLs在体内的分化以及它们随后向髓鞘形成性OLs的谱系进展。因此，我们对生物活性物质进行了药代动力学预测，随后进行了它们与Smo的分子对接和分子动力学模拟。从1289种姜黄素类似物和80种印度人参衍生的生物活性物质中，最佳对接配体分别被鉴定为具有PubChem ID 68815167和25880的化合物。这些配体的分子动力学模拟进一步得出结论，印度人参生物活性物质25880与Smo具有最佳活性。该化合物可被视为一种潜在的先导分子，用于与Smo进行激动性相互作用并激活它，以启动其下游信号级联反应，从而促进OL分化。
