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hERG Blockade Prediction by Combining Site Identification by Ligand Competitive Saturation and Physicochemical Properties. 结合配体竞争饱和度和物理化学性质的位点识别预测hERG阻断。
IF 2.1 Pub Date : 2022-09-01 DOI: 10.3390/chemistry4030045
Himanshu Goel, Wenbo Yu, Alexander D MacKerell

Human ether-a-go-go-related gene (hERG) potassium channel is well-known contributor to drug-induced cardiotoxicity and therefore an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to predict hERG toxicity. Availability of the recent published cryogenic electron microscopy (cryo-EM) structure for the hERG channel opened the prospect for using structure-based simulation and docking approaches for hERG drug liability predictions. In recent time, the idea of combining structure- and ligand-based approaches for modeling hERG drug liability has gained momentum offering improvements in predictability when compared to ligand-based QSAR practices alone. The present article demonstrates uniting the structure-based SILCS (site-identification by ligand competitive saturation) approach in conjunction with physicochemical properties to develop predictive models for hERG blockade. This combination leads to improved model predictability based on Pearson's R and percent correct (represents rank-ordering of ligands) metric for different validation sets of hERG blockers involving diverse chemical scaffold and wide range of pIC50 values. The inclusion of the SILCS structure-based approach allows determination of the hERG region to which compounds bind and the contribution of different chemical moieties in the compounds to blockade, thereby facilitating the rational ligand design to minimize hERG liability.

人类乙醚-a-go-go相关基因(hERG)钾通道是众所周知的药物诱导心脏毒性的因素,因此在进行候选药物安全性评估时是一个极其重要的靶点。基于配体的方法与定量结构活性关系(QSAR)分析已经发展到预测hERG毒性。最近发表的hERG通道的低温电子显微镜(cryo-EM)结构的可用性为使用基于结构的模拟和对接方法进行hERG药物负荷预测开辟了前景。近年来,与单独基于配体的QSAR实践相比,结合基于结构和配体的方法来建模hERG药物负性的想法获得了动力,提供了可预测性的改进。本文展示了基于结构的SILCS(通过配体竞争饱和进行位点识别)方法与物理化学性质相结合,以开发hERG阻断的预测模型。这种组合导致基于Pearson’s R和正确率(表示配体的排序)度量的模型可预测性的提高,这些度量涉及不同的化学支架和大范围的pIC50值的hERG阻滞剂的不同验证集。包含基于SILCS结构的方法可以确定化合物结合的hERG区域以及化合物中不同化学成分对阻断的贡献,从而促进合理的配体设计以最小化hERG责任。
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引用次数: 3
The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D2 Agonist [18F]MCL-524. 多巴胺D2激动剂[18F]MCL-524的非无水、最低碱性合成。
IF 2.1 Pub Date : 2021-09-01 Epub Date: 2021-09-09 DOI: 10.3390/chemistry3030075
James A H Inkster, Anna W Sromek, Vamsidhar Akurathi, John L Neumeyer, Alan B Packard

The dopamine D2 agonist MCL-524 is selective for the D2 receptor in the high-affinity state (D2high), and, therefore, the PET analogue, [18F]MCL-524, may facilitate the elucidation of the role of D2high in disorders such as schizophrenia. However, the previously reported synthesis of [18F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [18F]MCL-524 using a "non-anhydrous, minimally basic" (NAMB) approach. In this method, [18F]F- is eluted from a small (10-12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:H2O (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [18F]F- recovery. The tosylated precursor (1 mg) in 0.9 mL anhydrous acetonitrile was added directly to the eluate, without azeotropic drying, and the solution was heated (150 °C/15 min). The catechol was then deprotected with the Lewis acid In(OTf)3 (10 equiv.; 150 °C/20 min). In contrast to deprotection with protic acids, Lewis-acid-based deprotection facilitated the efficient removal of byproducts by HPLC and eliminated the need for SPE extraction prior to HPLC purification. Using the NAMB approach, [18F]MCL-524 was obtained in 5-9% RCY (decay-corrected, n = 3), confirming the utility of this improved method for the multistep synthesis of [18F]MCL-524 and suggesting that it may applicable to the synthesis of other 18F-labeled radiotracers.

多巴胺D2激动剂MCL-524对处于高亲和力状态(D2high)的D2受体是选择性的,因此,PET类似物[18F]MCL-524,可以促进阐明D2high在精神分裂症等疾病中的作用。然而,先前报道的[18F]MCL-524的合成被证明难以复制,并且缺乏实验细节。因此,我们使用“非无水、最低碱性”(NAMB)方法开发了[18F]MCL-524的新合成方法。在该方法中,[18F]F-用在7:3MeCN:H2O(0.1mL)中的甲苯磺酸四乙基铵(2.37mg)从小型(10-12mg)捕获和释放柱中洗脱,而不是最常用于[18F]F-回收的碱性碳酸盐或碳酸氢盐溶液。将甲苯磺酰化的前体(1 mg)在0.9 mL无水乙腈中直接加入洗脱液中,无需共沸干燥,并加热溶液(150°C/15分钟)。然后用路易斯酸In(OTf)3(10当量;150°C/20分钟)对邻苯二酚进行脱保护。与用质子酸脱保护相反,基于路易斯酸的脱保护促进了通过HPLC有效去除副产物,并消除了在HPLC纯化之前对SPE提取的需要。使用NAMB方法,在5-9%RCY(衰变校正,n=3)中获得[18F]MCL-524,证实了这种改进方法在[18F]MCL-524的多步合成中的实用性,并表明它可以应用于其他18F标记的放射性示踪剂的合成。
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引用次数: 0
Reactive Sterol Electrophiles: Mechanisms of Formation and Reactions with Proteins and Amino Acid Nucleophiles. 反应性甾醇亲电试剂:形成机制及与蛋白质和氨基酸亲核试剂的反应。
IF 2.1 Pub Date : 2020-06-01 DOI: 10.3390/chemistry2020025
Ned A Porter, Libin Xu, Derek A Pratt

Radical-mediated lipid oxidation and the formation of lipid hydroperoxides has been a focal point in the investigation of a number of human pathologies. Lipid peroxidation has long been linked to the inflammatory response and more recently, has been identified as the central tenet of the oxidative cell death mechanism known as ferroptosis. The formation of lipid electrophile-protein adducts has been associated with many of the disorders that involve perturbations of the cellular redox status, but the identities of adducted proteins and the effects of adduction on protein function are mostly unknown. Both cholesterol and 7-dehydrocholesterol (7-DHC), which is the immediate biosynthetic precursor to cholesterol, are oxidizable by species such as ozone and oxygen-centered free radicals. Product mixtures from radical chain processes are particularly complex, with recent studies having expanded the sets of electrophilic compounds formed. Here, we describe recent developments related to the formation of sterol-derived electrophiles and the adduction of these electrophiles to proteins. A framework for understanding sterol peroxidation mechanisms, which has significantly advanced in recent years, as well as the methods for the study of sterol electrophile-protein adduction, are presented in this review.

自由基介导的脂质氧化和脂质氢过氧化物的形成一直是许多人类病理研究的焦点。脂质过氧化长期以来一直与炎症反应有关,最近已被确定为氧化细胞死亡机制的核心原则,即铁下垂。脂类亲电蛋白加合物的形成与许多涉及细胞氧化还原状态扰动的疾病有关,但加合蛋白的特性以及加合对蛋白质功能的影响大多是未知的。胆固醇和7-脱氢胆固醇(7-DHC)都可被臭氧和氧中心自由基等物质氧化。7-DHC是胆固醇的直接生物合成前体。自由基链反应的产物混合物特别复杂,最近的研究扩大了形成的亲电化合物的集合。在这里,我们描述了与固醇衍生的亲电试剂的形成和这些亲电试剂对蛋白质的内聚有关的最新进展。本文综述了近年来对甾醇过氧化机制的研究进展,以及甾醇亲电-蛋白内合反应的研究方法。
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引用次数: 14
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