Coevolution and subsite decomposition for the design of resistance-evading HIV-1 protease inhibitors.
Coevolution and subsite decomposition for the design of resistance-evading HIV-1 protease inhibitors.
复制标题
用于设计逃避耐药性的 HIV-1 蛋白酶抑制剂的协同进化和亚位点分解。
DOI：
10.1006/jmbi.1998.2579
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Goodsell,DS
中科院分区：
文献类型：
--
作者：
Rosin,CD;Belew,RK;Walker,WL;Morris,GM;Olson,AJ;Goodsell,DS
Drug resistance sharply limits the effectiveness of human immunodeficiency virus (HIV) protease inhibitors in acquired immunodeficiency syndrome therapy. In previous work, we presented methods for design of resistance-evading inhibitors using a computational coevolution technique. Here, we report subsite decomposition experiments that examine the relative importance and roles of each subsite in HIV protease, and the constraints on robust inhibitor design that are imposed by possible resistance mutations in each subsite. The results identify several structural features of robust resistance-evading inhibitors for use in drug design, and show their basis in the constraints imposed by the range of allowable mutation in the protease. In particular, the results identify the P3 and P3′ sites as being particularly sensitive to protease mutation: inhibitors designed to fill the S3 and S3′ sites of the wild-type protease will be susceptible to viral resistance, but inhibitors with side-chains smaller than a phenylalanine residue at P3 and P3′, preferably medium-sized amino acids in the range from valine to leucine and isoleucine residues, will be more robust in the face of protease resistance mutation.
