Rutenber E, Fauman E B, Keenan R J, Fong S, Furth P S, Ortiz de Montellano P R, Meng E, Kuntz I D, DeCamp D L, Salto R
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.
J Biol Chem. 1993 Jul 25;268(21):15343-6.
A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.
一种稳定的1型人类免疫缺陷病毒蛋白酶非肽抑制剂已被研发出来，其结合的立体化学结构通过晶体学三维结构测定得以确定。最初的化合物氟哌啶醇是通过使用形状互补算法对剑桥结构数据库进行计算筛选发现的。后续的修饰是一种非肽侧链先导物，它属于一类具有明确药理特性的化合物。这种氟哌啶醇的硫代缩酮衍生物和卤化物抗衡离子以一种不同于基于肽的抑制剂所观察到的模式结合在酶活性位点内。与该抑制剂共结晶的蛋白酶变体以最初基于计算机搜索所预测的方式结合。这些结构为该抑制剂后续的合成修饰提供了背景。
