Suppr超能文献

一种小分子探针诱导 HIV TAR RNA 形成一种构象,使其能够结合类似药物的片段。

A small-molecule probe induces a conformation in HIV TAR RNA capable of binding drug-like fragments.

机构信息

Department of Chemistry, University of Washington, Box 351700, Seattle, WA 98195, USA.

出版信息

J Mol Biol. 2011 Jul 29;410(5):984-96. doi: 10.1016/j.jmb.2011.03.039.

Abstract

The HIV-1 transactivation response (TAR) element-Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach toward screening fragments against RNA that uses a chemical probe to target the Tat-binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe-RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher-affinity lead compounds for the inhibition of the TAR-Tat interaction.

摘要

HIV-1 转录激活反应 (TAR) 元件-Tat 相互作用是治疗 HIV 感染的一个有潜在价值的靶点,但开发 TAR 结合抗病毒药物的努力尚未产生有希望进入临床开发的候选药物。在这项工作中,我们描述了一种针对 RNA 的筛选片段的新方法,该方法使用化学探针靶向 TAR 的 Tat 结合区域。该探针在筛选中发挥了两个关键作用:通过将 RNA 锁定在能够与其他片段结合的构象中,同时允许通过基于配体的 NMR 鉴定近端结合片段。使用这种方法,我们发现了六个新的 TAR 结合片段,其中三个片段根据实验 NMR 约束相对于探针-RNA 结构进行了对接。在我们基于数据的对接结构中功能基团的一致取向和所有片段的常见静电特性揭示了我们基于片段大小的筛选命中具有令人惊讶的选择性。这些模型进一步提出了连接策略,用于开发更高亲和力的先导化合物,以抑制 TAR-Tat 相互作用。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验