PDF(Pubmed)
Abstract：
Cordycepin, or 3\'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3\' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3\' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin\'s mechanism of action.
摘要：
虫草素,或3'-脱氧腺苷，是一种具有广谱生物活性的腺苷类似物。虫草素和腺苷之间的关键结构差异在于在核糖环的3'位不存在羟基。在管理时，虫草素可以在特定组织中进行酶转化，形成虫草素三磷酸。在这项研究中,我们对虫草素及其衍生物的结构特征进行了全面分析，除了分子动力学模拟外，还使用化学信息学和生物信息学工具将它们与内源性嘌呤代谢物进行对比。我们检验了虫草素三磷酸可以与腺苷酸环化酶的活性位点结合的假设。我们的分子动力学模拟结果显示，优于，三磷酸腺苷（ATP），内源性配体。这种相互作用可以通过作为在3'位置缺乏羟基的假ATP来减少环磷酸腺苷（cAMP）的产生，进行核苷酸环化所必需的。我们讨论了在肿瘤微环境中癌症和其他细胞可塑性的背景下的含义，比如癌症相关的成纤维细胞，内皮，和免疫细胞。这种相互作用可以通过防止由持续的cAMP信号驱动的免疫细胞的表型变化来唤醒抗肿瘤免疫。最后一个可能是未报道的分子机制，有助于解释有关虫草素作用机制的更多细节。
