Computational analysis of Plasmodium falciparum metabolism:: Organizing genomic information to facilitate drug discovery
Computational analysis of Plasmodium falciparum metabolism:: Organizing genomic information to facilitate drug discovery
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DOI：
10.1101/gr.2050304
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发表时间：
2004-05-01
期刊：
影响因子：
7
通讯作者：
Altman, RB
中科院分区：
文献类型：
--
作者：
Yeh, W;Hanekamp, T;Altman, RB
为开发更有效的抗疟药物和疫苗确定新的靶点是疟原虫基因组计划的主要目标。然而，决定哪些基因产物是理想的药物/疫苗靶标仍然是一项艰巨的任务。目前，系统地破坏疟原虫中的每一个基因在技术上是具有挑战性的。因此，我们开发了一种计算方法来优先考虑潜在目标。途径/基因组数据库（PGDB）将途径信息与关于生物体的完整基因组的信息整合。我们已经构建了PlasmoCyc，恶性疟原虫3D 7的PGDB，使用其注释的基因组序列。除了基因组数据库中提供的注释外，我们使用GeneQuiz注释系统将956个额外的注释添加到注释为“假设”的蛋白质中。我们将一种新的计算算法应用于PlasmoCyc来识别216“阻塞点酶。所有三种临床验证的药物靶点都是“阻塞点酶”。文献中有生物学证据的建议药物靶点中，共有87.5%是阻塞点反应。因此，鉴定阻塞点酶代表了鉴定潜在代谢药物靶标的一种系统方法。
Identification of novel targets for the development of more effective antimalarial drugs and vaccines is a primary goal of the Plasmodium genome project. However, deciding which gene products are ideal drug/vaccine targets remains a difficult task. Currently, a systematic disruption of every single gene in Plasmodium is technically challenging. Hence, we have developed a computational approach to prioritize potential targets. A pathway/genome database (PGDB) integrates pathway information with information about the complete genome of an organism. We have constructed PlasmoCyc, a PGDB for Plasmodium falciparum 3D7, using its annotated genomic sequence. In addition to the annotations provided in the genome database, we add 956 additional annotations to proteins annotated as "hypothetical" using the GeneQuiz annotation system. We apply a novel computational algorithm to PlasmoCyc to identify 216 "chokepoint enzymes." All three clinically validated drug targets are "chokepoint enzymes. A total of 87.5% of proposed drug targets with biological evidence in the literature are chokepoint reactions. Therefore, identifying chokepoint enzymes represents one systematic way to identify potential metabolic drug targets.