计算机辅助发现抗HIV药物。
Computer-aided discovery of anti-HIV agents.
作者信息
Jorgensen William L
机构信息
Department of Chemistry, Yale University, New Haven, CT 06520-8107, United States.
出版信息
Bioorg Med Chem. 2016 Oct 15;24(20):4768-4778. doi: 10.1016/j.bmc.2016.07.039. Epub 2016 Jul 21.
Abstract
A review is provided on efforts in our laboratory over the last decade to discover anti-HIV agents. The work has focused on computer-aided design and synthesis of non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) with collaborative efforts on biological assaying and protein crystallography. Numerous design issues were successfully addressed including the need for potency against a wide range of viral variants, good aqueous solubility, and avoidance of electrophilic substructures. Computational methods including docking, de novo design, and free-energy perturbation (FEP) calculations made essential contributions. The result is novel NNRTIs with picomolar and low-nanomolar activities against wild-type HIV-1 and key variants that also show much improved solubility and lower cytotoxicity than recently approved drugs in the class.
摘要
本文综述了我们实验室在过去十年中发现抗HIV药物的研究工作。这项工作主要集中在计算机辅助设计和合成HIV-1逆转录酶非核苷抑制剂（NNRTIs），并与生物测定和蛋白质晶体学方面展开合作。成功解决了许多设计问题，包括对多种病毒变体的效力需求、良好的水溶性以及避免亲电子亚结构。对接、从头设计和自由能扰动（FEP）计算等计算方法做出了重要贡献。结果是得到了新型NNRTIs，它们对野生型HIV-1和关键变体具有皮摩尔和低纳摩尔活性，并且与该类中最近批准的药物相比，溶解性有了很大改善，细胞毒性也更低。
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