分子机理证明 S-COMT 与次生植物代谢物一起分析时是很有前景的治疗受体

IF 3.2 4区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY Journal of the Indian Chemical Society Pub Date : 2024-09-20 DOI:10.1016/j.jics.2024.101391
Deepanshu Garg, Aarya Vashishth, Maharsh Jayadeep Jayawant, Virupaksha A. Bastikar
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引用次数: 0

摘要

重度抑郁症(MDD)和其他精神疾病使人衰弱,影响着全球数百万人。儿茶酚-O-甲基转移酶(COMT)是一种调节大脑中多巴胺和去甲肾上腺素分解的酶,已成为这些疾病的潜在治疗靶点。本研究利用计算技术探讨了植物次生代谢物对 S-COMT 的抑制潜力。COMT 有两种异构体:膜结合型 COMT(MB-COMT)和可溶性 COMT(S-COMT),前者主要存在于大脑神经元中,后者存在于外周组织中。S-COMT 对调节神经递质和维持认知功能至关重要,尤其是在前额叶皮质中。研究表明,S-COMT 变异可能与抑郁症、精神分裂症和其他精神疾病的发病有关。目前的 COMT 抑制剂往往存在局限性,因此有必要探索新的治疗策略。本研究采用硅学方法研究植物次生代谢物作为潜在的 S-COMT 抑制剂。在此,我们介绍了 S-COMT 蛋白结构的检索和验证,随后进行了分子对接模拟,以确定与受体活性位点结合亲和力最强的植物化合物。同时还分析了参与这些相互作用的关键氨基酸残基。此外,还进行了分子动力学模拟,以评估得分最高的蛋白质配体复合物在 100-ns 时间范围内的稳定性。结果探讨了配体在活性位点内结合的稳定性及其对 S-COMT 受体整体构象的影响。我们的研究结果凸显了这些植物提取化合物的治疗潜力。有必要进一步开展体外和体内研究,以验证它们在治疗 S-COMT 相关疾病的潜在临床应用中的有效性和安全性。
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Molecular Mechanics Demonstrate S-COMT as promising therapeutic receptor when analyzed with secondary plant metabolites
Major depressive disorder (MDD) and other psychiatric conditions are debilitating illnesses affecting millions globally. Catechol-O-methyltransferase (COMT), an enzyme that regulates dopamine and norepinephrine breakdown in the brain, has emerged as a potential therapeutic target for these disorders. This study explores the inhibitory potential of plant secondary metabolites against S-COMT using computational techniques. COMT exists in two isoforms: membrane-bound COMT (MB-COMT), primarily found in brain neurons, and soluble COMT (S-COMT), present in peripheral tissues. S-COMT, particularly in the prefrontal cortex, is crucial for regulating neurotransmitters and maintaining cognitive function. Studies suggest S-COMT variants might be linked to the development of depression, schizophrenia, and other psychiatric disorders. Current COMT inhibitors often suffer from limitations, necessitating the exploration of novel therapeutic strategies. This study employed in-silico methods to investigate plant secondary metabolites as potential S-COMT inhibitors. Here, we describe the S-COMT protein structure retrieval and validation, followed by molecular docking simulations to identify plant compounds with the strongest binding affinity to the receptor's active site. Key amino acid residues involved in these interactions were also analyzed. Furthermore, molecular dynamics simulations were conducted to assess the stability of the top-scoring protein-ligand complexes over a 100-ns timeframe. The results explored the stability of ligand binding within the active site and its impact on the overall conformation of the S-COMT receptor. Our findings highlight promising therapeutic potential for these plant-derived compounds. Further in vitro and in vivo studies are warranted to validate their efficacy and safety for potential clinical applications in treating S-COMT-related disorders.

Subjects

Bioinformatics and Computational Biology, Proteomics, Neurogenerative Diseases.
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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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