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计算机辅助发现自然化合物,以ADAR2 dsRBD2-RNA接口为目标,并对全长ADAR2蛋白结构进行计算建模

Carolyn N Ashley¹, Emmanuel Broni¹, Michelle Pena-Martinez¹

¹Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA.

International journal of molecular sciences

|May 14, 2025

概括

研究人员确定了天然化合物,可以通过抑制ADAR2RNA结合来治疗间皮瘤. 这些化合物显示出作为新型中瘤治疗药物的潜力,为这种攻击性癌症提供了希望.

科学领域:

计算化学和药物发现
瘤学和癌症治疗学
分子生物学和RNA结合蛋白.

背景情况:

间皮瘤是一种具有不良预后的侵袭性癌症,通常与接触石棉有关.
抑制作用于dsRNA 2 (ADAR2) 结合RNA的腺氨酸脱氨酶显示出对间皮瘤治疗的前景.
目前对于中瘤的有效治疗方法有限.

研究的目的:

为了识别来自传统中医 (TCM) 的天然化合物,可以与ADAR2的RNA结合域 (dsRBD2) 结合并抑制.
评估这些化合物的药物相似性,安全性和结合亲和力.
为进一步研究开发高质量的ADAR2模型.

主要方法:

对TCM化合物的分子对接到ADAR2 dsRBD2.
分子力学Poisson-Boltzmann表面积 (MM/PBSA) 计算的结合亲和力.
分子动力学 (MD) 模拟来分析蛋白质-配体-RNA相互作用.
开发完整的ADAR2模型.

主要成果:

八种化合物对ADAR2 dsRBD2.2具有很高的结合亲和力.
四种化合物 (ZINC000085597263,ZINC000085633079,ZINC000014649947,ZINC000034512861) 在RNA基质的存在下显示出负的结合亲缘关系.
关键残留物 (Val164,Met165,Lys209,Lys212) 被确定为关键的联体结合,表明抑制ADAR2RNA结合.
预测的生物活动和与已知的抗癌剂的结构相似性表明,它对间皮瘤有治疗潜力.

结论:

已识别的天然化合物具有抑制ADAR2RNA结合的潜力,为间皮瘤提供了一种新的治疗策略.
这些化合物在结构上与现有的抗癌药物有关,因此需要进一步研究和优化用于间皮瘤治疗.
开发的ADAR2模型为未来的蛋白质工程和治疗开发提供了宝贵的见解.

关键词:

阿达尔 (ADAR) 是一个叫做ADAR的词.货币货币/PBSA计算方法编辑RNA的RNA编辑计算机辅助的药物发现.在全长ADAR2中.同源性建模的同源性建模半质瘤 (Mesothelioma) 是一种中质瘤.分子动力学模拟,分子动力学模拟自然化合物自然化合物

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