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激酶组的更新与阐释:将激酶作为疟疾潜在药物靶点的优先级排序

Update and elucidation of kinomes: Prioritization of kinases as potential drug targets for malaria.

作者信息

Borba Joyce Villa Verde Bastos, Silva Arthur de Carvalho E, do Nascimento Marília Nunes, Ferreira Letícia Tiburcio, Rimoldi Aline, Starling Luísa, Ramos Pablo Ivan Pereira, Costa Fabio Trindade Maranhão, Andrade Carolina Horta

机构信息

LabMol - Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmácia, Universidade Federal de Goiás (UFG), Goiânia, Brazil.

Laboratory of Tropical Diseases - Prof. Dr. Luiz Jacintho da Silva, Department of Genetics Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas (UNICAMP), Campinas, SP, Brazil.

出版信息

Comput Struct Biotechnol J. 2022 Jul 8;20:3708-3717. doi: 10.1016/j.csbj.2022.07.003. eCollection 2022.

Abstract

Malaria is a tropical disease caused by spp. and transmitted by the bite of infected mosquitoes. Protein kinases (PKs) play key roles in the life cycle of the etiological agent of malaria, turning these proteins attractive targets for antimalarial drug discovery campaigns. As part of an effort to understand parasite signaling functions, we report the results of a bioinformatics pipeline analysis of PKs of eight species. To date, no and kinome assemble has been conducted. We classified, curated and annotated predicted kinases to update kinomes published to date, as well as report for the first time the kinomes of and . Overall, from 76 to 97 PKs were identified among all spp. kinomes. Most of the kinases were assigned to seven of nine major kinase groups: AGC, CAMK, CMGC, CK1, STE, TKL, OTHER; and the group FIKK. About 30% of kinases have been deeply classified into group, family and subfamily levels and only about 10% remained unclassified. Furthermore, updating and comparing the kinomes of and allowed for the prioritization and selection of kinases as potential drug targets that could be explored for discovering new drugs against malaria. This integrated approach resulted in the selection of 37 protein kinases as potential targets and the identification of investigational compounds with moderate activity against asexual (3D7 and Dd2 strains) stages that could serve as starting points for the search of potent antimalarial leads in the future.

摘要

疟疾是一种由疟原虫属物种引起的热带疾病,通过受感染蚊子的叮咬传播。蛋白激酶(PKs)在疟疾病原体的生命周期中发挥关键作用,使这些蛋白质成为抗疟疾药物研发活动的有吸引力的靶点。作为理解寄生虫信号传导功能努力的一部分,我们报告了对八种疟原虫物种的蛋白激酶进行生物信息学管道分析的结果。迄今为止,尚未进行过疟原虫和疟原虫激酶组的组装。我们对预测的激酶进行了分类、整理和注释,以更新迄今已发表的疟原虫激酶组,同时首次报告了疟原虫和疟原虫的激酶组。总体而言,在所有疟原虫物种的激酶组中鉴定出76至97个蛋白激酶。大多数激酶被归类到九个主要激酶组中的七个:AGC、CAMK、CMGC、CK1、STE、TKL、OTHER;以及FIKK组。约30%的激酶已被深入分类到组、家族和亚家族水平,只有约10%仍未分类。此外,更新和比较疟原虫和疟原虫的激酶组有助于对激酶进行优先级排序和选择,作为潜在的药物靶点,可用于探索抗疟疾新药。这种综合方法导致选择了37种蛋白激酶作为潜在靶点,并鉴定出对无性疟原虫(3D7和Dd2菌株)阶段具有中等活性的研究性化合物,这些化合物可作为未来寻找强效抗疟疾先导物的起点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6223/9293725/b268aca8d609/ga1.jpg

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