Development of phenolic small molecule inhibitors of PfATP6, a Plasmodium calcium ATPase

项目总结/摘要 疟疾是一种由疟原虫寄生虫引起的传染病， 健康问题。PfATP 6是一种存在于恶性疟原虫中的钙转运酶， 被确定为新抗疟药物的靶点。因此，特异性和有效的PfATP 6抑制剂 有望成为新一代抗疟疾药物。它们也可能作为研究工具， 阐明酶的生理作用。目前已知仅有几种PfATP 6抑制剂， 它们中的大多数由于其高度的结构复杂性而受到限制，从而限制了它们的可用性。一 值得注意的例外是一组结构简单的酚类化合物，它们最初是在 图书馆屏幕由于它们具有氢醌和萘醌骨架，因此可以合成 这是一个很大的优势。该项目的重点是设计和 新型PfATP 6抑制剂的表征，最初关注对苯二酚/萘醌 脚手架本研究的长期目标是全面了解 PfATP 6与小抑制分子在分子水平上的相互作用。作为第一步 该提案的目的是鉴定和表征抑制剂，这些抑制剂是未来的良好候选物。 发展初步数据表明，开发新的PfATP 6抑制剂的基础上， 靶向支架是可实现的目标。为实现这一目标，将追求以下两个具体目标： 目的1：建立有效PfATP 6抑制的结构要求。最初的图书馆有50- 60种潜在抑制剂将从供应商处获得或合成。这些化合物将首先 在用纯化的PfATP 6进行的抑制测定中，然后在用活寄生虫进行的存活测定中进行评价。的 结果将提供结构-活性关系，其鉴定对抑制作用至关重要的结构元件。 目的2：使用抑制剂结合位点的结构模型鉴定新的抑制剂支架。 PfATP 6。应用计算技术，目前未知的抑制剂结合的结构模型 网站将生成。在验证模型后，将利用其预测能力， 化合物文库的虚拟筛选以鉴定替代抑制剂类型。最终目标是增加 PfATP 6抑制剂库的结构多样性，通过添加具有新支架的化合物。 拟议的研究是创新的，因为它将是第一个系统地探索小 分子PfATP 6抑制剂的实验和计算方法的组合。是 重要的是，它提供了开发新的抗疟疾剂所必需的基本信息， 有价值的新研究工具。此外，该项目将使PI能够发起和维持一个值得称赞的 萨克拉门托州立大学的一项研究计划，让来自代表性不足的少数民族的学生参与到一个多元的 学科药物设计项目。

Project Summary/Abstract Malaria, an infectious disease caused by Plasmodium parasites, continues to pose a serious global health problem. PfATP6, a calcium-transporting enzyme present in Plasmodium falciparum, has been identified as a target for new antimalarial drugs. Therefore, specific and potent inhibitors of PfATP6 hold promise as a new generation of antimalarial agents. They may also be of value as research tools for the elucidation of the enzyme’s physiological roles. Only a few PfATP6 inhibitors are presently known and most of them suffer from limitations due to their high structural complexity, restricting their availability. A notable exception is a group of structurally simple phenolic compounds that were originally identified in library screens. As they feature hydroquinone and naphthoquinone scaffolds, they can be synthesized straightforwardly, which is a major advantage. The proposed project focusses on the design and characterization of novel PfATP6 inhibitors, with initial focus on the hydroquinone/naphthoquinone scaffolds. The long term goal of this research is to obtain a comprehensive understanding of the interactions between PfATP6 and small inhibitory molecules at the molecular level. As a first step, the objective of this proposal is to identify and characterize inhibitors that are good candidates for future development. Preliminary data suggest that the development of new PfATP6 inhibitors based on the targeted scaffolds is an achievable goal. To reach it, the following two Specific Aims will be pursued: Aim 1: Establish the structural requirements for effective PfATP6 inhibition. An initial library of 50- 60 potential inhibitors will be obtained from vendors or be synthesized. These compounds will first be evaluated in inhibition assays with purified PfATP6 and then in viability assays with living parasites. The results will furnish structure-activity relationships that identify structural elements critical for inhibition. Aim 2: Identify novel inhibitor scaffolds using structural models of the inhibitor binding site of PfATP6. Applying computational techniques, structural models of the currently unknown inhibitor binding site will be generated. After having validated the models, their predictive capabilities will be employed for virtual screens of compound libraries to identify alternative inhibitor types. The ultimate goal is to increase the structural diversity of the PfATP6 inhibitor pool by adding compounds with new scaffolds. The proposed research is innovative because it will be the first to systematically explore small molecule PfATP6 inhibitors by a combination of experimental and computational approaches. It is significant as it provides fundamental information necessary to develop novel anti-malarial agents and valuable new research tools. Moreover, the project will enable the PI to initiate and sustain a meritorious research program at Sacramento State, engaging students from underrepresented minorities in a multi- disciplinary drug design project.