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Antiprotozoal QSAR modelling for trypanosomiasis (Chagas disease) based on thiosemicarbazone and thiazole derivatives
Journal of Molecular Graphics and Modelling ( IF 2.9 ) Pub Date : 2020-12-07 , DOI: 10.1016/j.jmgm.2020.107821
Diana L Nossa González 1 , Jovanny A Gómez Castaño 1 , Wilson E Rozo Núñez 1 , Pablo R Duchowicz 2
Affiliation  

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a neglected endemic infection that affects around 8 million people worldwide and causes 12,000 premature deaths per year. Traditional chemotherapy is limited to the nitro-antiparasitic drugs Benznidazole and Nifurtimox, which present serious side effects and low long-term efficacy. Several research efforts have been made over the last decade to find new chemical structures with better effectiveness and tolerance than standard anti-Chagas drugs. Among these, new sets of thiosemicarbazone and thiazole derivatives have exhibited potent in vitro activity against T. cruzi, especially for its extracellular forms (epimastigote and trypomastigote). In this work, we have developed three antiprotozoal quantitative structure-relationship (QSAR) models for Chagas disease based on the in vitro activity data reported as IC50 (μM) and CC50 (μM) over the last decade, particularly by Lima-Leite’s group in Brazil. The models were developed using the replacement method (RM), a technique based on Multivariable Linear Regression (MLR), and external and internal validation methodologies, like the use of a test set, Leave-one-Out (LOO) cross-validation and Y-Randomization. Two of these QSAR models were developed for trypomastigotes form of the parasite Trypanosoma cruzi, one based on IC50 and the other on CC50 data; while the third QSAR model was developed for its epimastigotes form based on CC50 activity. Our models presented sound statistical parameters that endorses their prediction capability. Such capability was tested for a set of 13 hitherto-unknown structurally related aromatic cyclohexanone derivatives.



中文翻译:

基于硫半脲和噻唑衍生物的锥虫病(恰加斯病)的抗原生动物QSAR建模

由原生动物寄生虫克氏锥虫引起的南美锥虫病仍然是一种被忽视的地方性感染,全世界感染该病的人数约为800万人,每年造成12,000人过早死亡。传统化学疗法仅限于硝基抗寄生虫药苯并咪唑和硝呋替莫,它们显示出严重的副作用且长期疗效低。在过去的十年中,已经进行了数项研究工作,以寻找比标准的抗南美锥虫病药物具有更好的效力和耐受性的新化学结构。其中,新的硫半脲和噻唑衍生物在体外显示出对克氏锥虫的有效活性,尤其是其细胞外形式(表鞭毛和锥虫)。在这项工作中,我们根据过去十年中IC 50(μM)和CC 50(μM)报告的体外活性数据,特别是利马-莱特氏(Lima-Leite's )的研究,为查加斯病开发了三种抗原虫定量结构关系(QSAR)模型集团在巴西。使用替代方法(RM),基于多变量线性回归(MLR)的技术以及外部和内部验证方法(例如使用测试集,留一法(LOO)交叉验证和Y随机化。这些QSAR模型中的两个是针对锥虫锥虫锥虫的形式而开发的,一个基于IC 50另一个关于CC 50数据;而第三个QSAR模型是根据CC 50活性为其副鞭毛形式开发的。我们的模型提出了合理的统计参数,这些参数支持了它们的预测能力。针对一组13种迄今未知的结构相关的芳族环己酮衍生物进行了测试。

更新日期:2020-12-14
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