使用酸抑制HIV- 1蛋白酶
Ian W Windsor1, Michael J Palte, John C Lukesh
1Department of Chemistry , Massachusetts Institute of Technology , Cambridge , Massachusetts 02139 , United States.
Journal of the American Chemical Society
|October 23, 2018
概括
酸可以形成强键,从而产生一种新的HIV-1蛋白酶抑制剂. 这种新型的抑制剂具有20倍的亲和力,
科学领域:
- 医学化学
- 结构生物学
- 计算化学
背景情况:
- 酸通常用于共价相互作用.
- 它们的非对应性识别潜力尚未得到充分探索.
- 在抗逆转录病毒治疗中,HIV-1蛋白酶抑制剂至关重要.
研究的目的:
- 探索酸作为非共价识别剂.
- 开发一种具有增强亲和力的新型HIV-1蛋白酶抑制剂.
- 研究含酸的结合相互作用.
主要方法:
- 达鲁纳维尔的酸类似物的设计和合成.
- 使用蛋白酶结合试验进行亲和度测量.
- 进行X射线结晶学以确定结合模式.
- 密度函数理论 (DFT) 计算以分析键特性.
主要成果:
- 在达鲁纳维尔中用酸替代氨酸,蛋白酶亲和度增加了20倍.
- 酸部分形成了三个关键的键,包括Asp30/Asn30.
- 该抑制剂对耐药的D30NHIV-1蛋白酶变体保持了很高的亲和力.
- 观察到短,共价BOH·OC键,由DFT证实.
结论:
- 酸是药物设计中非共价识别的有效部分.
- 这项研究提供了一种具有酸组的强效HIV-1蛋白酶抑制剂.
- 酸为开发具有高亲和力的小分子配体提供了多功能平台.
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