Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
Design, synthesis, protein-ligand X-ray structure, and biological evaluation of a series of novel macrocyclic human immunodeficiency virus-1 protease inhibitors to combat drug resistance.
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DOI：
10.1021/jm900695w
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Mitsuya H
中科院分区：
文献类型：
--
作者：
Ghosh AK;Kulkarni S;Anderson DD;Hong L;Baldridge A;Wang YF;Chumanevich AA;Kovalevsky AY;Tojo Y;Amano M;Koh Y;Tang J;Weber IT;Mitsuya H
介绍了一系列非肽类大环HIV蛋白水解酶抑制剂的结构设计、合成及生物活性评价。这些抑制剂被设计成有效地填充S1‘S2’亚基的疏水口袋，并保持与蛋白质骨架的所有主要氢键，类似于Darunavir(1)或抑制剂2。评估了环大小、甲基取代和大环环结构内不饱和的影响。总体而言，环状抑制剂的活性明显高于非环同系物，饱和环的活性低于不饱和类似物，并显示出对10元和13元大环环的偏好。甲基取代基的加入导致了活性的降低。抑制剂14b和14c都表现出明显的酶抑制和抗病毒活性，并且它们对多药耐药的HIV-1变异体具有很强的活性。抑制剂2和14c的蛋白质-配体X射线结构为研究配体结合部位的相互作用提供了重要的分子信息。
The structure-based design, synthesis and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1′ S2′ subsites and retain all major hydrogen bonding with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogs and a preference for 10 and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in the reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity and they exerted potent activity against multi-drug resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions.
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影响因子：
2.9
作者：
Panigrahi, Sunil K.;Desiraju, Gautam R.
通讯作者：
Desiraju, Gautam R.
影响因子：
16.6
作者：
SCHWAB, P;FRANCE, MB;GRUBBS, RH
通讯作者：
GRUBBS, RH
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444903008126
发表时间：
2003-07-01
影响因子：
2.2
作者：
Potterton, E;Briggs, P;Dodson, E
通讯作者：
Dodson, E
DOI：
10.1093/protein/7.3.309
发表时间：
1994-03-01
期刊：
PROTEIN ENGINEERING
影响因子：
--
作者：
GUSTCHINA, A;SANSOM, C;WEBER, IT
通讯作者：
WEBER, IT