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狗牙根植物甾醇靶向MAPK3和PARP1对抗上皮性卵巢癌的分子机制:一种多方面的计算方法

Molecular Mechanism of Cynodon dactylon Phytosterols Targeting MAPK3 and PARP1 to Combat Epithelial Ovarian Cancer: A Multifaceted Computational Approach.

作者信息

Balkrishna Acharya, Sharma Yoganshi, Dabas Shakshi, Arya Vedpriya, Dabas Anurag

机构信息

Patanjali Herbal Research Department, Patanjali Research Foundation, Haridwar, 249405, Uttarakhand, India.

University of Patanjali, Patanjali Yogpeeth, Haridwar, 249405, Uttarakhand, India.

出版信息

Cell Biochem Biophys. 2024 Sep;82(3):2625-2650. doi: 10.1007/s12013-024-01375-w. Epub 2024 Jul 3.

Abstract

Epithelial Ovarian Cancer (EOC) presents a global health concern, necessitating the development of innovative therapeutic strategies to combat its impact. This study was employed to investigate the unexplored therapeutic efficacy of Cynodon dactylon phytochemicals against EOC using a multifaceted computational approach. A total of 19 out of 89 rigorously curated phytochemicals were assessed as potential drug targets via ADMET profiling, while protein-protein interaction analysis scrutinized the top 20 hub genes among 264 disease targets, revealing their involvement in cancer-related pathways and underscoring their significance in EOC pathogenesis. In molecular docking, Stigmasterol acetate showed the highest binding affinity (-10.9 kcal/mol) with Poly [ADP-ribose] polymerase-1 (PDB: 1UK1), while Arundoin and Beta-Sitosterol exhibited strong affinities (-10.4 kcal/mol and -10.1 kcal/mol, respectively); additionally, Beta-Sitosterol interacting with Mitogen-activated protein kinase 3 (PDB: 4QTB) showed a binding affinity of -10.1 kcal/mol, forming 2 hydrogen bonds and a total of 10 bonds with 10 residues. Molecular dynamics simulations exhibited the significant structural stability of the Beta-Sitosterol-4QTB complex with superior binding free energy (-36.61 kcal/mol) among the three complexes. This study identified C. dactylon phytosterols, particularly Beta-Sitosterol, as effective in targeting MAPK3 and PARP1 to combat EOC, laying the groundwork for further experimental validation and drug development efforts.

摘要

上皮性卵巢癌(EOC)是一个全球性的健康问题,因此需要开发创新的治疗策略来对抗其影响。本研究采用多方面的计算方法,研究狗牙根植物化学物质对EOC尚未探索的治疗效果。通过ADMET分析,在89种经过严格筛选的植物化学物质中,共有19种被评估为潜在的药物靶点,而蛋白质-蛋白质相互作用分析则仔细研究了264个疾病靶点中的前20个枢纽基因,揭示了它们参与癌症相关途径,并强调了它们在EOC发病机制中的重要性。在分子对接中,醋酸豆甾醇与聚[ADP-核糖]聚合酶-1(PDB:1UK1)表现出最高的结合亲和力(-10.9 kcal/mol),而芦竹素和β-谷甾醇表现出较强的亲和力(分别为-10.4 kcal/mol和-10.1 kcal/mol);此外,β-谷甾醇与丝裂原活化蛋白激酶3(PDB:4QTB)相互作用时表现出-10.1 kcal/mol的结合亲和力,形成2个氢键,并与10个残基总共形成10个键。分子动力学模拟显示,β-谷甾醇-4QTB复合物在三种复合物中具有显著的结构稳定性,结合自由能优异(-36.61 kcal/mol)。本研究确定狗牙根植物甾醇,特别是β-谷甾醇,在靶向MAPK3和PARP1以对抗EOC方面有效,为进一步的实验验证和药物开发工作奠定了基础。

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