Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8.
Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8.
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药效学和分子对接研究揭示了通过靶向 HSPB8 对抗神经退行性疾病的潜在新型抗抑郁药
DOI：
10.2147/dddt.s101929
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Ali S
中科院分区：
文献类型：
--
作者：
Sehgal SA;Mannan S;Ali S
CMT （Charcot-Marie-Tooth）病是一种遗传性周围神经肌肉疾病，其特征是周围神经的长度依赖性和进行性变性，导致肌肉无力。研究表明，突变的HSPB8可能导致抑郁症、神经退行性疾病和周围神经功能不正常，导致神经肌肉疾病，如CMT。在目前的工作中，采用虚拟筛选和分子对接研究的混合方法，然后进行同源性建模和药效团鉴定。通过对处方抗抑郁药物理化性质的二维相似性搜索进行详细筛选分析。LigandScout用于确定新分子和药效团性质。在这项研究中，我们报道了三种与HSPB8具有最大结合亲和力的新化合物。对接分析表明，Met37、Ser57、Ser58、Trp60、Thr63、Thr114、Lys115、Asp116、Gly117、Val152、Val154、Leu186、Asp189、Ser190、Gln191和Glu192是配体与受体相互作用的关键残基。我们的分析表明帕罗西汀是一种有效的靶向HSPB8的化合物。所选化合物比所选药物类似物具有更高的有效能量分数。此外，位点定向诱变可能对进一步分析结合袋具有重要意义。基于计算机方法的新发现可能对抗抑郁症和CMT的有效药物设计具有重要意义。
Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand–receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT.