Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.
Structure-based evaluation of non-nucleoside inhibitors with improved potency and solubility that target HIV reverse transcriptase variants.
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DOI：
10.1021/jm501908a
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发表时间：
2015-03-26
影响因子：
7.3
通讯作者：
Anderson KS
中科院分区：
文献类型：
--
作者：
Frey KM;Puleo DE;Spasov KA;Bollini M;Jorgensen WL;Anderson KS
开发具有抗HIV逆转录酶（RT）变体活性的新型非核苷抑制剂（NNRTI）对于克服治疗失败至关重要。非核苷类逆转录酶抑制剂结合在RT的变构口袋中，距离活性位点约10 μ m。儿茶酚二醚化合物系列的早期类似物对具有野生型RT的HIV毒株具有皮摩尔活性，但对具有单Y181 C和双K103 N/Y181 C突变的变体失去效力。根据基于结构和计算研究的指导，去除儿茶酚芳基环系统上化合物1的5-Cl取代产生了新的类似物化合物2，其保持了对Y181 C和K103 N/Y181 C变体的更大效力和更好的溶解度（510 μg/mL）。确定了野生型、Y181 C和K103 N/Y181 C RT与化合物1和2的复合物的晶体结构，以理解这些发现的结构基础。结构的比较揭示了Y181 C突变使化合物1的结合模式不稳定，并破坏了与口袋中残基的相互作用。化合物2在野生型和突变体结构中保持相同的构象，除了与NNRTI结合口袋的几种相互作用之外。比较六种晶体结构将有助于理解化合物结合模式和未来邻苯二酚二醚系列的优化。
The development of novel non-nucleoside inhibitors (NNRTIs) with activity against variants of HIV reverse transcriptase (RT) is crucial for overcoming treatment failure. The NNRTIs bind in an allosteric pocket in RT ∼10 Å away from the active site. Earlier analogues of the catechol diether compound series have picomolar activity against HIV strains with wild-type RT but lose potency against variants with single Y181C and double K103N/Y181C mutations. As guided by structure-based and computational studies, removal of the 5-Cl substitution of compound 1 on the catechol aryl ring system led to a new analogue compound 2 that maintains greater potency against Y181C and K103N/Y181C variants and better solubility (510 μg/mL). Crystal structures were determined for wild-type, Y181C, and K103N/Y181C RT in complex with both compounds 1 and 2 to understand the structural basis for these findings. Comparison of the structures reveals that the Y181C mutation destabilizes the binding mode of compound 1 and disrupts the interactions with residues in the pocket. Compound 2 maintains the same conformation in wild-type and mutant structures, in addition to several interactions with the NNRTI binding pocket. Comparison of the six crystal structures will assist in the understanding of compound binding modes and future optimization of the catechol diether series.
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影响因子：
3.3
作者：
Johnson BC;Pauly GT;Rai G;Patel D;Bauman JD;Baker HL;Das K;Schneider JP;Maloney DJ;Arnold E;Thomas CJ;Hughes SH
通讯作者：
Hughes SH
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
7.3
作者：
Bollini, Mariela;Domaoal, Robert A.;Thakur, Vinay V.;Gallardo-Macias, Ricardo;Spasov, Krasimir A.;Anderson, Karen S.;Jorgensen, William L.
通讯作者：
Jorgensen, William L.
影响因子：
7.3
作者：
Das, K;Clark, AD;Arnold, E
通讯作者：
Arnold, E
DOI：
10.1107/s0907444998004284
发表时间：
1998-09-01
影响因子：
2.2
作者：
Esnouf, RM;Ren, JS;Stuart, DI
通讯作者：
Stuart, DI