Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.
Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease.
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DOI：
10.1021/jm301519z
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发表时间：
2013-02-14
影响因子：
7.3
通讯作者：
Weber, Irene T.
中科院分区：
文献类型：
--
作者：
Zhang, Hongmei;Wang, Yuan-Fang;Shen, Chen-Hsiang;Agniswamy, Johnson;Rao, Kalapala Venkateswara;Xu, Chun-Xiao;Ghosh, Arun K.;Harrison, Robert W.;Weber, Irene T.
GRL-0519（1）是HIV-1蛋白酶（PR）的有效抗病毒抑制剂，在P2处具有三-四氢呋喃（tris-THF）。结合动力学数据分析了抑制剂1与单取代突变体PRR 8 Q、PRD 30 N、PRI 50 V、PRI 54 M和PRV 82 A复合物的高分辨率X射线晶体结构。PRI 50 V中较小的缬氨酸侧链消除了与抑制剂和其他亚基的疏水相互作用，这与60倍更差的抑制一致。PRD 30 N中的Asn 30显示与相邻残基的相互作用改变，抑制作用差18倍。突变V82 A和I54 M显示出补偿性结构变化，与6-7倍的低抑制一致。PRR 8 Q中的Gln 8用氢键相互作用取代了野生型Arg 8的离子相互作用，而没有显著改变抑制作用。Gly 48的羰基氧在所有结构中显示出两种替代构象，这可能是由于S2亚位点中的大的tris-THF基团的紧密配合，与1对抗性病毒的高抗病毒功效一致。
GRL-0519 (1) is a potent antiviral inhibitor of HIV-1 protease (PR) possessing tris-tetrahydrofuran (tris-THF) at P2. The high resolution X-ray crystal structures of inhibitor 1 in complexes with single substitution mutants PRR8Q, PRD30N, PRI50V, PRI54M, and PRV82A were analyzed in relation to kinetic data. The smaller valine side chain in PRI50V eliminated hydrophobic interactions with inhibitor and the other subunit consistent with 60-fold worse inhibition. Asn30 in PRD30N showed altered interactions with neighboring residues and 18-fold worse inhibition. Mutations V82A and I54M showed compensating structural changes consistent with 6-7-fold lower inhibition. Gln8 in PRR8Q replaced the ionic interactions of wild type Arg8 with hydrogen bond interactions without changing the inhibition significantly. The carbonyl oxygen of Gly48 showed two alternative conformations in all structures likely due to the snug fit of the large tris-THF group in the S2 subsite in agreement with high antiviral efficacy of 1 on resistant virus.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
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影响因子：
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影响因子：
11.5
作者：
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通讯作者：
Faulds, D
影响因子：
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作者：
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通讯作者：
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