Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules.
Three-dimensional QSAR of human immunodeficiency virus (I) protease inhibitors. 1. A CoMFA study employing experimentally-determined alignment rules.
复制标题
人类免疫缺陷病毒（I）蛋白酶抑制剂的三维QSAR。
DOI：
10.1021/jm00078a003
复制
发表时间：
1993
影响因子：
7.3
通讯作者：
Marshall,GR
中科院分区：
文献类型：
--
作者：
Waller,CL;Oprea,TI;Giolitti,A;Marshall,GR
人类免疫缺陷病毒（Human immunodeficiency virus，HIV）是获得性免疫缺陷综合征（acquired immunodeficiency syndrome，AIDS）的病原体，其作用是通过宿主制备的病毒多聚蛋白的遗传方向来表达的。HIV-1蛋白酶是由病毒编码的天冬氨酸蛋白酶，负责加工gag和gag-pol基因多蛋白。已经证明，在病毒复制的蛋白水解步骤进行治疗干预可以产生不成熟和非感染性的病毒后代。1 '2利用从早期对肾素和其他天冬氨酸蛋白酶的研究中获得的知识，3' 4已经开发了许多基于肽的抑制剂，它们模拟了底物的易断裂酰胺键水合后形成的四面体中间体。已经报道了几种过渡态类似物，其包含不可裂解的还原酰胺、5酮亚甲基、6羟乙基-胺、7 '10他汀、1112去甲他汀、13或二羟基亚乙基14键作为电子等排键（图1）。这些类似物中的许多在体外表达亚纳摩尔活性，因此，在HIV感染的临床管理中可能有用。传统的结构-活性数据表明，S（或其等效物）-羟基非对映异构体在抑制剂的电子等排键中的优先性，
Human immunodeficiency virus (HIV) is the etiologic agent of acquired immunodeficiency syndrome (AIDS) which expresses its effects through the genetic direction of viral polyproteins prepared by the host. HI V-1 protease is the aspartic proteinase encoded by the virus responsible for the processing of the gag and gag-pol gene polyproteins. Therapeutic intervention at this proteolytic step of viral replication has been demonstrated to yield immature and noninfectious viral progeny. 1’2 Using the knowledge gained from earlier studies on renin and other aspartic protein-ases, 3’4 many peptide-based inhibitors havebeen developed which mimic the tetrahedral intermediate formed upon hydration of the scissile amide bonds of the substrate. Several transition-state analogs incorporating noncleav-able reduced amide, 5 ketomethylene, 6 hydroxyethyl-amine, 7'10 statine, 1112 norstatine, 13 or dihydroxyethylene14 linkages as the isosteric bond have been reported (Figure 1). Many of these analogs express subnanomolar activity in vitro and, therefore, are potentially useful in the clinical management of HIV infection. Conventional structure-activity data indicate a pref-erence for the S (or its equivalent)-hydroxyl diastereomer in the isosteric linkage of the inhibitor positioned between