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Benchmarking analysis of deleterious SNP prediction tools on CYP2D6 enzyme
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-03-09 , DOI: 10.1111/cbdd.13676 Karla Cristina do Vale Ferreira 1, 2 , Leonardo Ferreira Fialho 1 , Octávio Luiz Franco 1, 2, 3 , Sérgio Amorim de Alencar 1 , William Farias Porto 3, 4
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-03-09 , DOI: 10.1111/cbdd.13676 Karla Cristina do Vale Ferreira 1, 2 , Leonardo Ferreira Fialho 1 , Octávio Luiz Franco 1, 2, 3 , Sérgio Amorim de Alencar 1 , William Farias Porto 3, 4
Affiliation
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The cytochrome P450 family is composed of hemeproteins involved in the metabolic transformation of endogenous and exogenous substances. The CYP2D6 enzyme is responsible for the metabolism of ~25% of clinically used drugs and is mainly expressed in the liver. The CYP2D6 gene is known to have a large number of single nucleotide polymorphisms (SNPs). Nevertheless, these variations could modify the CYP2D6 enzyme's function, resulting in poor metabolizing or ultra‐extensive metabolizing phenotypes, when metabolism is slower or accelerated, respectively. Currently, there are several computational tools for predicting functional changes caused by genetic variations. Here, we evaluated the predictive power of 20 web servers using a data set of 37 CYP2D6 missense SNPs (2 neutral and 35 deleterious) previously reported in literature with enzymatic assays with the purified protein. The results suggest that the most appropriate tools for CYP2D6 SNP prediction are SDM and PoPMuSiC, which could aid in the classification of novel missense SNPs in this gene, providing the identification of mutations potentially associated with drug metabolism and pointing new directions for precise medicine.
中文翻译：
有害SNP预测工具对CYP2D6酶的基准分析
细胞色素P450家族由参与内源性和外源性物质代谢转化的血红蛋白组成。CYP2D6酶负责约25％的临床使用药物的代谢，并且主要在肝脏中表达。的CYP2D6基因，已知有大量的单核苷酸多态性（SNP）的。然而，这些变化可能会改变CYP2D6酶的功能，导致当代谢变慢或加速时，不良的代谢表型或超广泛的代谢表型。当前，有几种计算工具可用于预测由遗传变异引起的功能变化。在这里，我们使用37个CYP2D6数据集评估了20台Web服务器的预测能力先前在文献中使用纯化的蛋白质通过酶法测定报道的错义SNP（2个中性和35个有害）。结果表明，用于CYP2D6 SNP预测的最合适工具是SDM和PoPMuSiC，它们可以帮助对该基因中的新型错义SNP进行分类，从而提供与药物代谢相关的潜在突变的识别，并为精确医学指明新的方向。
更新日期：2020-03-09
中文翻译：
有害SNP预测工具对CYP2D6酶的基准分析
细胞色素P450家族由参与内源性和外源性物质代谢转化的血红蛋白组成。CYP2D6酶负责约25％的临床使用药物的代谢，并且主要在肝脏中表达。的CYP2D6基因，已知有大量的单核苷酸多态性（SNP）的。然而，这些变化可能会改变CYP2D6酶的功能，导致当代谢变慢或加速时，不良的代谢表型或超广泛的代谢表型。当前，有几种计算工具可用于预测由遗传变异引起的功能变化。在这里，我们使用37个CYP2D6数据集评估了20台Web服务器的预测能力先前在文献中使用纯化的蛋白质通过酶法测定报道的错义SNP（2个中性和35个有害）。结果表明，用于CYP2D6 SNP预测的最合适工具是SDM和PoPMuSiC，它们可以帮助对该基因中的新型错义SNP进行分类，从而提供与药物代谢相关的潜在突变的识别，并为精确医学指明新的方向。
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