Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning,ACS Medicinal Chemistry Letters

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Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2020-01-09 , DOI: 10.1021/acsmedchemlett.9b00586
Adriana Gambino ₁ , James C Burnett ₁ , Kazunori Koide ₁

Affiliation

Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood–brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.

中文翻译：

神经毒剂中毒解毒剂 2-解磷定的甲基扫描和修正结合模式

有机磷神经毒剂 (OPNA) 会抑制乙酰胆碱酯酶 (AChE)，尽管有《化学武器公约》军备控制条约，但它仍然对军事人员和平民构成威胁。2-解磷定（2-PAM）是目前美国食品和药物管理局批准用于治疗OPNA中毒的唯一治疗对策。然而，2-PAM 由于其亲水性和导致血脑屏障通透性差而没有中枢活性。因此，这些缺陷需要开发更疏水的类似物。具体而言，先前发表的 2-PAM 结构活性关系 (SAR) 研究中存在空白，因此难以合理设计同时具有更高渗透性和更有效的新型类似物。在这项研究中，我们有条不紊地对 2-PAM 的核心吡啶鎓进行了甲基扫描，以确定可以耐受额外空间体积和疏水性的环位置。随后，SAR 引导的分子对接被用于合理化 2-PAM 和报告的衍生物的亲水可行结合模式。总的来说，本文提供的数据提供了新的见解，可以促进更有效的 2-PAM 类似物的合理设计。

更新日期：2020-01-09

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