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首页> 外文期刊>Naturwissenschaften >Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design
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Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

机译：人类ABC转运蛋白ABCG2的药物基因组学：从功能评估到药物分子设计

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In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug–drug interactions. We recently developed methods for high-speed functional screening and quantitative structure–activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.
机译：在后基因组测序时代，新兴的基因组技术正在改变药物发现和开发的范式。尽管如此，药物发现和开发仍然是高风险和高风险的企业，时间表长且成本高。实际上，在临床前和开发阶段候选药物的消耗是药物设计中的主要问题。对于至少30％的候选药物，这种损耗是由于不良的药代动力学和毒性所致。因此，制药公司已开始认真地重新评估其当前的药物发现和开发策略。有鉴于此，我们建议基于转运机制的设计可能有助于创造新的，具有药代动力学优势的药物，因此，应将其视为药物设计策略的重要组成部分。相互作用测试可以执行基于酶和/或细胞的药物转运蛋白，可以极大地促进药物开发并预测药物与药物的相互作用。我们最近开发了用于高速功能筛选和定量构效关系分析的方法，以研究ABC转运蛋白的底物特异性，并评估遗传多态性对其功能的影响。这些方法将提供一种筛选合成和天然化合物的实用工具，并且这些数据可以应用于新药的分子设计。在这篇综述文章中，我们概述了人类ABC转运蛋白ABCG2和新的喜树碱类似物的遗传多态性，它们可以规避与AGCG2相关的癌症多药耐药性。

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  • 来源
    《Naturwissenschaften》 |2005年第10期|451-463|共13页
  • 作者

    Toshihisa Ishikawa; Ai Tamura; Hikaru Saito; Kanako Wakabayashi; Hiroshi Nakagawa;

  • 作者单位

    Department of Biomolecular Engineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology;

    Department of Biomolecular Engineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology;

    Department of Biomolecular Engineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology;

    Department of Biomolecular Engineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology;

    Department of Biomolecular Engineering Graduate School of Bioscience and Biotechnology Tokyo Institute of Technology;

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