Reich S H, Melnick M, Davies J F, Appelt K, Lewis K K, Fuhry M A, Pino M, Trippe A J, Nguyen D, Dawson H
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA.
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3298-302. doi: 10.1073/pnas.92.8.3298.
A class of potent nonpeptidic inhibitors of human immunodeficiency virus protease has been designed by using the three-dimensional structure of the enzyme as a guide. By employing iterative protein cocrystal structure analysis, design, and synthesis the binding affinity of the lead compound was incrementally improved by over four orders of magnitude. An inversion in inhibitor binding mode was observed crystallographically, providing information critical for subsequent design and highlighting the utility of structural feedback in inhibitor optimization. These inhibitors are selective for the viral protease enzyme, possess good antiviral activity, and are orally available in three species.
一类强效的人免疫缺陷病毒蛋白酶非肽类抑制剂已通过以该酶的三维结构为指导进行设计。通过反复进行蛋白质共晶体结构分析、设计和合成，先导化合物的结合亲和力逐步提高了四个多数量级。通过晶体学观察到抑制剂结合模式的反转，这为后续设计提供了关键信息，并突出了结构反馈在抑制剂优化中的作用。这些抑制剂对病毒蛋白酶具有选择性，具有良好的抗病毒活性，并且在三个物种中均可口服。
