Three-Dimensional HIV RNA Genome Targeted Drug Leads

描述（由申请人提供）：该项目的总体目标是通过基于三维RNA结构的商业可用化合物的计算筛选，开发有前途的药物先导物，利用HIV-1基因组部分的3D结构与选定的RNA靶标结合。候选物质是小的水溶性、非肽、非核苷酸的有机化合物。这些化合物也代表了后续化学修饰以增强其药物性能的有前途的支架。该项目需要改进有效靶向RNA的方法。这包括使众所周知的DOCK程序对靶向RNA更有用。它还需要继续开发一种新的程序，使筛选更小的化合物数据库（多达10,000）允许诱导与受体匹配。然而，即使在目前的阶段，我们对使用这种方法来发现与重要的HIV RNA结构结合的新的先导化合物非常感兴趣，从而可以开发成药物。购买最有希望的计算“命中”并通过我们开发的各种分析（包括核磁共振）测试与目标RNA的结合。实验将继续进行，以确定与TAR RNA和接吻环双链结合的化合物，接吻环双链对出芽病毒粒子中基因组RNA双链的组装至关重要。要检查的化合物包括已经或正在合成的几种吩噻嗪，以建立与TAR结合的结构-活性关系；吩噻嗪具有低毒性和良好的生物利用度，是一种很有前途的药物开发支架。我们将开发与RNA结合的低分子量化合物库，这些化合物具有良好的生物利用度、低毒性和连接能力。接吻环二聚体转化为线状二聚体的机制，是出芽病毒粒子组装所必需的，将使用一种新发现的小分子激动剂来研究，这种激动剂可以促进核衣壳蛋白NCp7的转化。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop promising drug leads via three-dimensional RNA structure based computational screening of commercially available compounds for binding to selected RNA targets utilizing the 3D structure of portions of the HIV-1 genome. Candidates are small water-soluble, nonpeptide, nonnucleotide organic compounds. These compounds should also represent promising scaffolds for subsequent chemical modification to enhance their pharmaceutical properties. The project entails work on improving the methodology for efficient targeting of RNA. This includes working to make the well-known DOCK program more useful for targeting RNA. It also entails continued development of a new program that enables screening of a smaller database of compounds (up to 10,000) permitting induced fit with the receptor. However, we are quite interested in using the methodology even at its current stage to discover new lead compounds that bind to important HIV RNA structures and thus could be developed into drugs. The most promising computational "hits" are purchased and tested for binding to the target RNA via various assays we have developed, including NMR. Experiments will continue on compounds already identified to bind to TAR RNA and to the kissing loop duplex that is essential for assembly of the genomic RNA duplex in the budding virion. Among compounds to be examined are several phenothiazines that have been or are being synthesized to establish a structure-activity relationship for binding to TAR; phenothiazine is a promising scaffold for drug development due to low toxicity and good bioavailability. A library of low molecular weight compounds, with good bioavailability and low toxicity and the capability of being linked, that have been found to bind RNA will be developed. The mechanism of the transformation of the kissing loop dimer to the linear dimer, required for assembly of the budding virion, will be studied using a newly found small molecule agonist that promotes the transformation as does the nucleocapsid protein NCp7.