Chloroethylagelastatin A (CEAA) is an analogue of agelastatin A (AA), a natural alkaloid derived from a marine sponge. It is under development for therapeutic use against brain tumors as it has excellent central nervous system (CNS) penetration and pre-clinical therapeutic activity against brain tumors. Recently, AA was shown to inhibit protein synthesis by binding to the ribosomal A-site. In this study, we developed a novel virtual screening platform to perform a comprehensive screening of various AA analogues showing that AA analogues with proven therapeutic activity including CEAA have significant ribosomal binding capacity whereas therapeutically inactive analogues show poor ribosomal binding and revealing structural fingerprint features essential for drug-ribosome interactions. In particular, CEAA was found to have greater ribosomal binding capacity than AA. Biological tests showed that CEAA binds the ribosome and contributes to protein synthesis inhibition. Our findings suggest that CEAA may possess ribosomal inhibitor activity and that our virtual screening platform may be a useful tool in discovery and development of novel ribosomal inhibitors.

中文翻译：

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虚拟筛选平台将氯乙基麦司他汀 A 鉴定为潜在的核糖体抑制剂

氯乙基吉拉司他汀 A (CEAA) 是吉司司他汀 A (AA) 的类似物，后者是一种源自海绵的天然生物碱。它正在开发用于脑肿瘤的治疗用途，因为它具有出色的中枢神经系统（CNS）渗透性和针对脑肿瘤的临床前治疗活性。最近，AA 被证明可以通过与核糖体 A 位点结合来抑制蛋白质合成。在本研究中，我们开发了一种新型虚拟筛选平台，对各种 AA 类似物进行全面筛选，结果表明，具有已证实治疗活性的 AA 类似物（包括 CEAA）具有显着的核糖体结合能力，而无治疗活性的类似物则显示出较差的核糖体结合能力，并揭示了对治疗至关重要的结构指纹特征。药物-核糖体相互作用。特别是，CEAA 被发现比 AA 具有更大的核糖体结合能力。生物学测试表明，CEAA 与核糖体结合，有助于抑制蛋白质合成。我们的研究结果表明，CEAA 可能具有核糖体抑制剂活性，并且我们的虚拟筛选平台可能是发现和开发新型核糖体抑制剂的有用工具。