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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Crystal structure of O-Acetylserine sulfhydralase (OASS) isoform 3 from Entamoeba histolytica: Pharmacophore-based virtual screening and validation of novel inhibitors
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Crystal structure of O-Acetylserine sulfhydralase (OASS) isoform 3 from Entamoeba histolytica: Pharmacophore-based virtual screening and validation of novel inhibitors

机译：来自entamoeba组织olytica的O-乙酰丝氨酸巯基巯基巯基磺胺酸盐酶（余数）的晶体结构：基于药物的虚拟筛选和新型抑制剂的验证

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摘要

The L-cysteine is crucial for growth, survival, defense against oxidative stress, and pathogenesis of Entamoeba histolytica. The de novo biosynthesis of L-cysteine in E. histolytica, has a two-step pathway, where O-acetylserine sulfhydrylase (OASS) catalyses the last step by converting OAS to L-cysteine. This pathway is absent in humans and hence represents a promising target for novel therapeutics. E. histolytica expresses three isoforms of OASS and knockdown studies showed the importance of these enzymes for the survival of the pathogen. Here, we report the crystal structure of OASS isoform 3 from E. histolytica to 1.54 A resolution. The active site geometries and kinetics of EhOASS3 and EhOASS1 structures were found to be very similar. Small-molecule libraries were screened against EhOASS3 and compounds were shortlisted based on the docking scores. F3226-1387 showed best inhibition with IC50 of 38 mu M against EhOASS3 and was able to inhibit the growth of the organism to 72%. (c) 2020 Elsevier Masson SAS. All rights reserved.
机译：L-半胱氨酸是人体生长，生存，对抗氧化应激防御和发病阿米巴的关键。在大肠杆菌中L-半胱氨酸的DE Novo生物合成，具有两步的途径，其中O-乙酰碱巯基酶（臭氧）通过将OA转换为L-半胱氨酸来催化最后一步。这种途径在人类中不存在，因此代表了新的治疗方法的有希望的目标。 E. HistolyTICA表达了三种臭氧和敲低的研究表明这些酶对于病原体存活的重要性。在这里，我们将oas ofomorm 3的晶体结构从大o. histolytica报告为1.54分辨率。发现EHOASS3和EHOASS1结构的活跃场地几何形状和动力学非常相似。筛选小分子文库对EHOASS3筛选，并且基于对接分数来入围化合物。 F3226-1387表现出与Ehoass3对抗38 mu m的最佳抑制，并且能够抑制生物体的生长至72％。 （c）2020 Elsevier Masson SAS。版权所有。

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