Emerging new technology: QSAR analysis and MO Calculation to characterize interactions of protein kinase inhibitors with the human ABC transporter, ABCG2 (BCRP).
Emerging new technology: QSAR analysis and MO Calculation to characterize interactions of protein kinase inhibitors with the human ABC transporter, ABCG2 (BCRP).
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DOI：
10.2133/dmpk.25.72
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发表时间：
2010
影响因子：
2.1
通讯作者：
H. Saito;R. An;H. Hirano;T. Ishikawa
中科院分区：
文献类型：
--
作者：
H. Saito;R. An;H. Hirano;T. Ishikawa
蛋白激酶是治疗包括癌症在内的多种疾病的潜在药物靶点。特别是，特异性酪氨酸激酶抑制剂作为抑制恶性细胞生长和转移形成的新药正在迅速开发。这些新开发的酪氨酸激酶抑制剂大多是疏水的，因此可以迅速穿透细胞膜到达细胞内目标。然而，药物在细胞内的蓄积受到多种因素的调节，包括内流和外排以及代谢。在癌症化疗中，癌细胞中药物外排转运体的过度表达是导致多药耐药的主要原因，从而降低了抗癌药物的疗效。因此，基于转运机制的分子设计策略将为抗癌化疗提供有效的工具。为了建立一个分子模拟平台，以规避多药耐药和减少药物引起的不良反应，我们建立了人类abcg2 -药物相互作用的高速筛选、定量构效关系（QSAR）分析和量子化学计算方法，以优化导联。本文综述了基于转运机制的分子设计策略的最新进展。
Protein kinases are potential drug targets for the treatment of a variety of diseases, including cancer. In particular, specific tyrosine kinase inhibitors are rapidly being developed as new drugs for the inhibition of malignant cell growth and metastasis formation. Most of these newly developed tyrosine kinase inhibitors are hydrophobic and thus rapidly penetrate the cell membrane to reach intracellular targets. However, intracellular accumulation of a drug is regulated by multiple factors, including influx and efflux as well as metabolism. In cancer chemotherapy, overexpression of drug efflux transporters in cancer cells is a major cause of multidrug resistance that reduces the efficacy of anticancer drugs. Thus, the transport mechanism-based molecular design strategy would provide an effective tool for chemotherapy against cancer. To develop a platform for molecular modeling to circumvent multidrug resistance and reduce drug-induced adverse effects, we established methods for high-speed screening for human ABCG2-drug interactions, quantitative structure-activity relationship (QSAR) analysis, and quantum chemical calculation for lead optimization. This review addresses recent advances in the strategy of transport mechanism-based molecular design.