Ring C S, Sun E, McKerrow J H, Lee G K, Rosenthal P J, Kuntz I D, Cohen F E
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143-0446.
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3583-7. doi: 10.1073/pnas.90.8.3583.
The lack of an experimentally determined structure of a target protein frequently limits the application of structure-based drug design methods. In an effort to overcome this limitation, we have investigated the use of computer model-built structures for the identification of previously unknown inhibitors of enzymes from two major protease families, serine and cysteine proteases. We have successfully used our model-built structures to identify computationally and to confirm experimentally the activity of nonpeptidic inhibitors directed against important enzymes in the schistosome [2-(4-methoxybenzoyl)-1-naphthoic acid, Ki = 3 microM] and malaria (oxalic bis[(2-hydroxy-1-naphthylmethylene)hydrazide], IC50 = 6 microM) parasite life cycles.
目标蛋白质缺乏通过实验确定的结构常常限制了基于结构的药物设计方法的应用。为了克服这一限制，我们研究了使用计算机构建的模型结构来鉴定来自两个主要蛋白酶家族（丝氨酸蛋白酶和半胱氨酸蛋白酶）的酶的先前未知抑制剂。我们已成功使用我们构建的模型结构通过计算鉴定并通过实验确认了针对血吸虫（2-(4-甲氧基苯甲酰基)-1-萘甲酸，Ki = 3 microM）和疟疾（草酸双[(2-羟基-1-萘基亚甲基)酰肼]，IC50 = 6 microM）寄生虫生命周期中重要酶的非肽类抑制剂的活性。
