Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds.
Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds.
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多重耐药 HIV-1 蛋白酶与两种有效抗疟化合物复合物的晶体结构。
DOI：
10.1016/j.bbrc.2012.03.096
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发表时间：
2012
影响因子：
3.1
通讯作者：
Gupta,Deepak
中科院分区：
文献类型：
--
作者：
Yedidi,RavikiranS;Liu,Zhigang;Wang,Yong;Brunzelle,JosephS;Kovari,IuliaA;Woster,PatrickM;Kovari,LadislauC;Gupta,Deepak
针对人类免疫缺陷病毒 1 型 (HIV-1) 天冬氨酰蛋白酶的野生型 (NL4-3) 和多重耐药临床分离株 769 (MDR) 变体，对疟疾天冬氨酰蛋白酶的两种有效抑制剂（化合物 1 和 2）进行了评估。酶抑制测定表明，1 和 2 对 NL4-3 的效力均优于对 MDR 蛋白酶的效力。解析并分析了与1和2复合的MDR蛋白酶的晶体结构。晶体分析表明，MDR 蛋白酶表现出典型的瓣开放构象（Gly48 至 Gly52），导致活性位点空腔整体扩张，进而导致抑制剂的不稳定结合。由于活性位点空腔的扩大，与 NL4-3 的对接模型相比，两种化合物均显示出与 MDR 蛋白酶的直接接触丧失。多个水分子显示出丰富的氢键网络，有助于两种晶体结构中 MDR 蛋白酶扭曲结合袋中配体结合的稳定性。 1 和 2 的对接分析显示两种化合物针对 MDR 的结合亲和力均降低，支持了我们的结构功能研究。因此，化合物 1 和 2 对 HIV-1 蛋白酶变体表现出有希望的抑制活性，因此是进一步开发以增强其对 NL4-3 以及 MDR HIV-1 蛋白酶变体的效力的良好候选者。
Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure–function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants.
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影响因子：
5.7
作者：
Martin, P;Vickrey, JF;Kovari, LC
通讯作者：
Kovari, LC
DOI：
10.1016/j.bbrc.2011.08.045
发表时间：
2011-09-09
影响因子：
3.1
作者：
Wang, Yong;Liu, Zhigang;Brunzelle, Joseph S.;Kovari, Iulia A.;Dewdney, Tamaria G.;Reiter, Samuel J.;Kovari, Ladislau C.
通讯作者：
Kovari, Ladislau C.
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
KNI-102，一种新型三肽 HIV 蛋白酶抑制剂，含有别苯基去甲他汀作为过渡态模拟物。
影响因子：
1.7
作者：
T. Mimoto;J. Imai;Shigeki Tanaka;N. Hattori;S. Kisanuki;K. Akaji;Y. Kiso
通讯作者：
Y. Kiso
DOI：
10.1107/s0907444907029125
发表时间：
2007-08-01
影响因子：
2.2
作者：
Heaslet, Holly;Rosenfeld, Robin;Stout, C. David
通讯作者：
Stout, C. David