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

疟原虫钙 ATP 酶 PfATP6 酚类小分子抑制剂的开发

• 批准号: 10627419
• 负责人: Stefan Franz Paula
• 金额: $ 14.2万
• 依托单位: CALIFORNIA STATE UNIVERSITY SACRAMENTO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627419
• 关键词: ATP phosphohydrolase; Antimalarials; Artemisinins; Binding Sites; Biological Assay; Biomedical Research; Ca(2+)-Transporting ATPase; Calcium; Chemicals; Chloroquine; Communicable Diseases; Communities; Complex; Computational Technique; Computing Methodologies; Culicidae; Dangerousness; Data; Development; Disease; Docking; Drug Design; Drug Targeting; Drug resistance; Education; Educational process of instructing; Effectiveness; Elements; Environment; Enzymatic Biochemistry; Enzyme Interaction; Enzymes; Foundations; Future; Generations; Goals; Group Meetings; Health; Homology Modeling; Human; Hydroquinones; Infection; Institution; Ion Transport; Knowledge; Libraries; Life; Ligands; Malaria; Measures; Mediating; Membrane; Methods; Minority Groups; Mission; Modeling; Modification; Molecular; Naphthoquinones; Nature; Organic Synthesis; Parasites; Pharmaceutical Preparations; Physiological; Plasmodium; Plasmodium falciparum; Preventive; Property; Publications; Quantitative Structure-Activity Relationship; Recombinants; Reporting; Research; Research Personnel; Role; Saccharomyces cerevisiae; Site-Directed Mutagenesis; Structural Models; Structure; Structure-Activity Relationship; Students; Therapeutic Agents; Training; Validation; Vendor; chemotherapy; combat; design; drug candidate; drug development; experimental study; fighting; global health; inhibitor; innovation; interest; molecular dynamics; molecular modeling; multidisciplinary; new therapeutic target; novel; novel therapeutics; programs; prototype; resistant strain; scaffold; skills; small molecule; small molecule inhibitor; student participation; symposium; tool; transmission process; undergraduate research; undergraduate student; underrepresented minority student; vaccine development; virtual

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.

项目摘要/摘要 疟疾是疟原虫寄生虫引起的一种传染病，继续构成严重的全球性 健康问题。 PFATP6是恶性疟原虫中存在的一种钙传输酶 被确定为新抗疟药的靶标。因此，PFATP6保持的特定和潜在抑制剂 承诺作为新一代的抗疟药。它们也可能是作为研究工具的价值 阐明酶的身体角色。仅显示了少数PFATP6抑制剂，并且 他们中的大多数人由于其较高的结构复杂性而受到限制，从而限制了它们的可用性。一个 一个值得注意的例外是一组最初鉴定出的结构简单的酚类化合物 图书馆屏幕。由于它们具有氢喹酮和萘酮脚手酮，因此可以合成 直接地，这是一个主要优势。拟议的项目着重于设计和 新型PFATP6抑制剂的表征，最初侧重于羟基酮/萘醌 脚手架。这项研究的长期目标是获得对 PFATP6与分子水平的小抑制分子之间的相互作用。作为第一步， 该建议的目的是识别和表征抑制剂，这些抑制剂是未来的良好候选者 发展。初步数据表明，基于 目标脚手架是一个可实现的目标。为了达到这一点，将追求以下两个具体目标： 目标1：确定有效PFATP6抑制的结构要求。最初的库为50- 60个潜在抑制剂将从供应商那里获得或合成。这些化合物首先是 用纯化的PFATP6进行抑制测定，然后在活寄生虫的可行性测定中进行评估。这 结果将提供结构活性关系，以确定对抑制至关重要的结构元素。 目标2：使用抑制剂结合位点的结构模型来识别新型抑制剂支架 PFATP6。应用计算技术，当前未知抑制剂结合的结构模型 站点将被生成。验证了模型后，他们的预测功能将成为员工 复合库的虚拟屏幕以识别替代抑制剂类型。最终目标是增加 PFATP6抑制剂池的结构多样性通过添加带有新脚手架的化合物。 拟议的研究具有创新性，因为它将是第一个系统地探索小型的研究 通过实验和计算方法的组合，分子PFATP6抑制剂。这是 意义重大，因为它提供了开发新型抗疟疾药物所需的基本信息，并且 重视新的研究工具。此外，该项目将使PI能够启动和维持功绩 萨克拉曼多州的研究计划，使来自代表性不足的少数民族的学生参与多个 纪律药物设计项目。