Interplay of inherent promiscuity and specificity in protein biochemical function with applications to drug discovery and exome analysis

蛋白质生化功能固有的混杂性和特异性与药物发现和外显子组分析应用的相互作用

• 批准号: 9270553
• 负责人: JEFFREY SKOLNICK
• 金额: $ 48.97万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-06 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270553
• 关键词: Active Sites; Adverse effects; Amino Acids; Binding; Binding Sites; Biochemical; Cell physiology; Cells; Chemicals; Disease; Enzymes; FDA approved; Failure; Genetic Variation; Human; Ligand Binding; Ligands; Mendelian disorder; Missense Mutation; Mutation; Pharmaceutical Preparations; Property; Proteins; Specificity; Structure; Tertiary Protein Structure; Testing; Variant; Wit; Work; base; design; disease diagnosis; drug discovery; exome; human disease; insight; protein function; protein structure; public health relevance; screening; small molecule; tool; virtual

 DESCRIPTION (provided by applicant): A gap exists as to how to interpret the information in the enormous number of sequenced human exomes in terms of the functional consequences of the observed variations in amino acids and their connection to human diseases. This gap also underlies the failure to develop drugs, without side effects, to treat these diseases. This failureis exacerbated by the fact that a given drug molecule binds to different proteins involved in numerous cellular processes. This proposal lays out the details as to how and why these problems occur, and in the context of protein structure, how our existing and proposed progress can help surmount them. We first elucidate the design principles underlying protein structure and function and then apply them to repurpose FDA approved drugs to treat Mendelian diseases and to identify the genetic variations underlying such diseases. We begin by examining whether the stereo chemical space of small molecule drugs and endogenous metabolites is complete and also the differences in the properties of drugs and metabolites. From these analyses, we will suggest how binding specificity might emerge from a highly promiscuous background. This might enable the design of better drugs with minimal side effects and a better understanding of how cells work. Employing these insights, we then develop better structure-based approaches to virtual ligand screening and enzyme function inference. The ability to predict enzymatic function is particularly essential as residue mutations associated wit loss of enzymatic function are the most important missense mutations associated with Mendelian disease. These approaches will use the conservation of ligand-protein microenvironments in stereochemically similar ligand binding sites or active sites in different proteins, regardless of their evolutionary relationship. We will explore the biochemical consequences of a class of enzymes that we discovered - dizymes, single domain proteins that perform two different enzymatic activities at two different active sites. For representative cases, we will experimentally test our predictions of ligand binding and enzymatic activity and their influence on cellular biochemical function. All developed tools will be combined in a comprehensive exome annotation approach. First, it will identify disease associated residue variations. Then, it will predict diseases a protein might be associated with and suggest the best protein targets. Finally, it will suggest what might be the best drugs to treat the disease.

 描述（由适用提供）：关于如何根据观察到的氨基酸变化的功能后果及其与人类疾病的联系的功能后果来解释测序人数增强的信息的差距。该差距还基于未能开发出无副作用的药物来治疗这些疾病的差异。这种失败加剧了以下事实，即给定的药物分子与参与许多细胞过程的不同蛋白质结合。该提案列出了有关这些问题如何以及为什么发生的细节，以及在蛋白质结构的背景下，我们现有和拟议的进度如何帮助他们。我们首先阐明了蛋白质结构和功能的设计原理，然后将其应用于改革FDA批准的药物以治疗孟德尔疾病并确定此类疾病的遗传变异。我们首先检查小分子药物和内源性代谢产物的立体化学空间是否完整，并且在药物和代谢产物的性质差异上也存在差异。从这些分析中，我们将提出结合特异性如何从高度混杂的背景中出现。这可能会使更好的药物设计具有最小的副作用，并更好地了解细胞的工作方式。然后，我们采用这些见解，开发出更好的基于结构的方法来进行虚拟配体筛选和酶功能推断。预测酶促功能的能力尤其重要，因为与酶功能的居住突变相关的丧失是与孟德尔氏病有关的最重要的错义突变。这些方法将在立体化学上相似的配体结合位点或不同蛋白质中的活性位点中使用配体 - 蛋白微环境的保存，无论其进化关系如何。我们将探索我们发现的一类酶的生化后果 - 二氮蛋白酶，单个结构域蛋白，它们在两个不同的活性位点上执行两种不同的酶促活性。用于代表案件， 我们将通过实验测试我们对配体结合和酶促活性的预测及其对细胞生化功能的影响。所有开发的工具将通过全面的外显子注释方法组合。首先，它将确定与疾病相关的居住变化。然后，它将预测蛋白质可能与蛋白质有关并提出最佳蛋白质靶标。最后，这将表明哪种可能是治疗该疾病的最佳药物。