Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies†,RSC Medicinal Chemistry

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Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors: binding mode insights through magnesium complexation and site-directed mutagenesis studies†
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2018-02-01 00:00:00 , DOI: 10.1039/c7md00600d
Vasanthanathan Poongavanam ₁ , Angela Corona ₂ , Casper Steinmann ₁ , Luigi Scipione ₃ , Nicole Grandi ₂ , Fabiana Pandolfi ₃ , Roberto Di Santo ₃ , Roberta Costi ₃ , Francesca Esposito ₂ , Enzo Tramontano _{2,

4} , Jacob Kongsted ₁

Affiliation

Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 μM with three hits exhibiting IC₅₀ values <10 μM. The most active compound, AA, inhibits HIV-1 RNase H with an IC₅₀ of 5.1 μM and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

中文翻译：

结构引导方法确定了一类新型 HIV-1 核糖核酸酶 H 抑制剂：通过镁络合和定点诱变研究了解结合模式†

持续性 HIV 感染需要终生治疗，每年新增 210 万例 HIV 感染，其中耐药突变传播率不断上升。这一事实需要不断、及时的努力，以识别和开发具有创新机制的新型艾滋病毒抑制剂。 HIV-1 逆转录酶 (RT) 相关核糖核酸酶 H (RNase H) 是唯一一种仍然缺乏有效抑制剂的病毒编码酶，尽管它是一个经过充分验证的靶标，其功能失效会损害病毒感染性。新药的鉴定是一个漫长而昂贵的过程，可以通过计算机方法加速。在本研究中，结构引导筛选与 Specs 数据库中基于相似性的搜索相结合，以确定一类新的 HIV-1 RNase H 抑制剂。在选择用于实验测试的 45 种化合物中，有 15 种将 RNase H 功能抑制在 100 μM 以下，其中 3 个命中表现出 IC ₅₀值 <10 id=29>AA ，抑制 HIV-1 RNase H 的 IC ₅₀为 5.1 μM，并表现出不依赖 Mg 的抑制模式。定点诱变研究为新发现的化合物的结合模式提供了有价值的见解；例如，化合物AA涉及与 Ala502、Lys503 和 Trp（406、426 和 535）形成的亲脂性口袋的广泛相互作用，以及与 Arg557 和高度保守的 RNase H 引物夹残基 Asn474 的极性相互作用。从这项工作中获得的结构见解为进一步先导优化提供了基础。

更新日期：2018-02-01

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