De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants
De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants
复制标题
DOI：
10.1021/jm0613121
复制
发表时间：
2007-05-17
影响因子：
7.3
通讯作者：
Hizi, Amnon
中科院分区：
文献类型：
--
作者：
Herschhorn, Alon;Lerman, Lena;Hizi, Amnon
我们使用分子模型设计了针对人类免疫缺陷病毒1型(HIV-1)逆转录酶(RT)野生型和耐药变异体的新的广谱抑制剂。首先，我们筛选了与四个RT结构(一个野生型和三个突变体)中的每一个相互作用的小片段。然后，将这些片段连接起来，构建一个支架分子。在合成的27个不同的化合物中，有4个化合物抑制RT的DNA聚合酶活性，IC50值低于10MU。化合物5f抑制RT的IC50值约为3.5MU，而抑制耐药RT变异体的效果比临床使用的药物奈韦拉平(11-cyclopropyl-5，11-dihydro-4-methyl-6H-dipyrido[3，2-b:2‘，3’-e][1，4]地西平-6-酮更有效。5F还抑制RT核糖核酸酶H的活性，IC50为20µM，因此，与奈韦拉平不同，5F针对这两种RT活性。因此，5f可作为开发新型RT抑制剂的先导，可用于抑制HIV-1的生长。
We used molecular modeling to design de novo broad-range inhibitors against wild type and drug-resistant variants of the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1). First, we screened for small fragments that would interact with each one of four RT structures (one wild type and three mutants). Then, these fragments were linked to build a scaffold molecule. Out of 27 different compounds that were synthesized, four inhibited the DNA polymerase activity of RT with IC50 values below 10 mu M. Compound 5f inhibited RT with an IC50 value of about 3.5 mu M, while inhibiting drug-resistant RT variants more efficiently than the clinically used drug, nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2 ',3 '-e][1,4]diazepin-6-one). 5f also inhibited the RT ribonuclease H activity with an IC50 of 20 mu M and therefore, unlike nevirapine, targets both RT activities. Accordingly, 5f can serve as lead for developing novel inhibitors against RT that may be used to suppress HIV-1 growth.