通过硅学鉴定和虚拟筛选发现针对 CMT2A 的强效治疗植物化学物质

IF 3.2 4区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY Journal of the Indian Chemical Society Pub Date : 2024-10-10 DOI:10.1016/j.jics.2024.101403
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引用次数: 0

摘要

Charcot-Marie-Tooth 神经病(CMT2A)是一组影响周围神经系统的单基因疾病。CMT2A 是一种由基因突变引起的疾病,其发病机制与线粒体动力学和轴突生物学功能受损有关。治疗方案仍然有限,只有少数药物和其他已获授权或开发不足的方法。我们采用了一种基于配体的虚拟筛选方法来确定潜在的 MFN 启动子。通过配体虚拟筛选技术,获得了 ZINC 数据库的天然化合物子集(n = 559600)并对其进行筛选。筛选出的前 200 个化合物中,有四个以上的特征与目标化合物相匹配。使用 Pyrx 软件进行分子对接分析。根据重要结合相互作用的数量和类型以及对接结果,我们选出了与目标蛋白质结合亲和力最好的前 20 种化合物。我们对通过分子对接分析确定的潜在配体进行了 3D-QSAR 分析,以预测其生物活性。利用 pEC50 和对接得分来确定潜在药物。ADMET 分析用于评估前两种药物的动力学特征。分子动力学模拟结果表明,排名第一的化合物 ZINC000005313168 具有较高的构象稳定性。根据对接结果和分子动力学模拟结果,在所研究的化合物中,ZINC000005313168 的硅学命中率最高。这些发现表明 ZINC000005313168 可用于治疗 CMT2A 疾病。需要进一步的体内和体外研究来考虑本分析结果。
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In silico identification and virtual screening to discover potent therapeutic phytochemicals against CMT2A
Charcot-Marie-Tooth (CMT2A) neuropathies are a set of monogenic diseases that affect the peripheral nervous system. The pathogenesis of CMT2A, a disease caused by genetic mutations, is linked to impaired mitochondrial dynamics and axonal biology. Therapeutic options are still limited, with only a few drugs and other authorized or underdeveloped approaches. A ligand-based virtual screening methodology was used to identify the potential MFN promoters. The natural compound subset of the ZINC database (n = 559600) was obtained and filtered using a ligand-based virtual screening technique. The top 200 compounds were identified to have more than four features that matched the target compound. Pyrx software was used to analyze the molecular docking. Based on the number and type of important binding interactions and docking results, we selected top-20 compounds with the best binding affinities for the targeted protein. 3D-QSAR analyses were performed on potential ligands identified through molecular docking analyses to predict biological activity. The pEC50 and docking scores were used to identify the potential drugs. The ADMET analysis was used to assess the kinetic characteristics of the top two drugs. According to molecular dynamics simulation, the top compound ZINC000005313168 showed high conformational stability. Based on docking results and MD findings, the best in silico hits among the compounds investigated was ZINC000005313168. These findings suggest that the compound ZINC000005313168 could be used to treat CMT2A disease. Further in vivo and in vitro studies are required to consider the present analyses.
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来源期刊
CiteScore
3.50
自引率
7.70%
发文量
492
审稿时长
3-8 weeks
期刊介绍: The Journal of the Indian Chemical Society publishes original, fundamental, theorical, experimental research work of highest quality in all areas of chemistry, biochemistry, medicinal chemistry, electrochemistry, agrochemistry, chemical engineering and technology, food chemistry, environmental chemistry, etc.
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