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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

Chemistry-Switzerland Pub Date : 2022-09-01 DOI: 10.3390/chemistry4030045

Himanshu Goel, Wenbo Yu, Alexander D MacKerell

{"title":"hERG Blockade Prediction by Combining Site Identification by Ligand Competitive Saturation and Physicochemical Properties.","authors":"Himanshu Goel, Wenbo Yu, Alexander D MacKerell","doi":"10.3390/chemistry4030045","DOIUrl":"https://doi.org/10.3390/chemistry4030045","url":null,"abstract":"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.","PeriodicalId":53216,"journal":{"name":"Chemistry-Switzerland","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9881610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10507199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Chemistry-Switzerland 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

{"title":"The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D2 Agonist [18F]MCL-524.","authors":"James A H Inkster, Anna W Sromek, Vamsidhar Akurathi, John L Neumeyer, Alan B Packard","doi":"10.3390/chemistry3030075","DOIUrl":"10.3390/chemistry3030075","url":null,"abstract":"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.","PeriodicalId":53216,"journal":{"name":"Chemistry-Switzerland","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2021-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41219982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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

Chemistry-Switzerland Pub Date : 2020-06-01 DOI: 10.3390/chemistry2020025

Ned A Porter, Libin Xu, Derek A Pratt

{"title":"Reactive Sterol Electrophiles: Mechanisms of Formation and Reactions with Proteins and Amino Acid Nucleophiles.","authors":"Ned A Porter, Libin Xu, Derek A Pratt","doi":"10.3390/chemistry2020025","DOIUrl":"https://doi.org/10.3390/chemistry2020025","url":null,"abstract":"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.","PeriodicalId":53216,"journal":{"name":"Chemistry-Switzerland","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3390/chemistry2020025","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9263361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 14