Advancing drug-lead and chemical-probe discovery using weighted-ensemble simulations and biophysical validation

使用加权集成模拟和生物物理验证推进先导药物和化学探针的发现

基本信息

批准号：
10189658
负责人：
Jacob D Durrant
金额：
$ 29.37万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10189658
关键词：
5&apos -exoribonuclease 7-methylguanosine Adoption Algorithms Antineoplastic Agents Basic Science Benchmarking Binding Binding Proteins Biological Assay Biology Biophysics Cells Chemicals Communities Complex Computer Assisted Computer software Crystallization Crystallography Data Development Disease Drug Design Drug Targeting Drug resistance FRAP1 gene Genetic Translation Growth Influenza Lead Licensing Ligand Binding Ligands Malignant Neoplasms Messenger RNA Methods Molecular Molecular Conformation Motion Neuraminidase Pathway interactions Pharmaceutical Preparations Pharmacology Phosphorylation Predisposition Production Protein Biosynthesis Proteins Publishing RNA Binding Research Resolution Ribosomal Proteins Ribosomes Sampling Shapes Signal Transduction Structure Testing Therapeutic Transcript Translations Validation Work X-Ray Crystallography anti-cancer base beta-Lactamase cell growth design drug discovery experimental study flexibility improved in silico inhibitor/antagonist innovation interest molecular dynamics novel novel therapeutics open source protein protein interaction resistance mutation response side effect simulation small molecule tool translation factor tripolyphosphate virtual virtual screening

项目摘要

Project Summary This project will study La-related protein 1 (LARP1), a molecular switch that allows cells to rapidly increase protein synthesis. LARP1 stores and protects the mRNA molecules required to make ribosomal proteins. In response to pro-growth signals or cancer, the mammalian target of rapamycin complex 1 (mTORC1) causes LARP1 to release its bound mRNAs. Ribosome production surges, leading to rapid increases in protein synthesis generally. Our strong preliminary data has led us to two central hypotheses. First, we hypothesize that LARP1- binding molecules (ligands) will interfere with the LARP1 mRNA-storage mechanism, thereby reducing protein synthesis. Second, we hypothesize that better understanding the flexibility of molecule-binding protein pockets—including LARP1 pockets—will improve rational ligand design. We will test these hypotheses in two aims. Aim 1 will create a new pocket-centric method for simulating proteins, called SubPEx. We will show that SubPEx can effectively reveal the flexibility of two well-characterized dynamic pockets (from TEM-1 b- lactamase and influenza neuraminidase). Aim 2 will use SubPEx, virtual screening, and biophysical experiments to identify new ligands that bind flexible LARP1 pockets. This work is significant in several ways. LARP1 ligands will serve as basic-science tools (chemical probes) to advance our understanding of LARP1 biology. Additionally, cancer requires extensive protein synthesis, so molecules that disrupt mTORC1-LARP1 signaling will serve as leads that will further the development of new therapies. Most mTORC1-pathway inhibitors bind mTOR itself. They are subject to resistance mutations and/or incomplete inhibition. LARP1 inhibition will provide a unique and innovative pharmacological approach. SubPEx itself will also be impactful. Many protein drug targets have highly flexible binding pockets, and successful structure-based drug design must account for that flexibility. Unlike other methods for exploring protein flexibility, SubPEx will focus computational effort on the binding pocket itself. Its permissive, open- source license will encourage adoption. We expect that many in the broader community will also use SubPEx to design ligands that bind their own disease-relevant proteins of interest.

项目概要该项目将研究 La 相关蛋白 1 (LARP1)，这是一种允许细胞快速增殖的分子开关。 LARP1 储存并保护制造核糖体蛋白所需的 mRNA 分子。对促生长信号或癌症的反应，雷帕霉素复合物 1 (mTORC1) 的哺乳动物靶标会导致 LARP1 释放其结合的 mRNA 产量激增，导致蛋白质快速增加。一般合成。我们强有力的初步数据使我们得出两个中心假设：首先，我们采用了 LARP1-。结合分子（配体）会干扰 LARP1 mRNA 存储机制，从而减少蛋白质其次，我们更好地理解了分子结合蛋白的灵活性。口袋（包括 LARP1 口袋）将改善合理的配体设计，我们将在两个方面测试这些假设。目标 1 将创建一种新的以口袋为中心的蛋白质模拟方法，称为 SubPEx。 SubPEx 可以有效地揭示两个充分表征的动态口袋的灵活性（来自 TEM-1 b- 目标 2 将使用 SubPEx、虚拟筛选和生物物理鉴定结合柔性 LARP1 口袋的新配体的实验。这项工作在多个方面具有重要意义，LARP1 配体将作为基础科学工具（化学探针）。此外，为了加深我们对 LARP1 生物学的理解，癌症需要大量的蛋白质合成。破坏 mTORC1-LARP1 信号传导的分子将作为线索，进一步开发新的大多数 mTORC1 通路抑制剂会结合 mTOR 本身，它们会发生耐药突变。和/或不完全抑制LARP1将提供独特且创新的药理学方法。 SubPEx 本身也将产生影响，许多蛋白质药物靶标具有高度灵活的结合袋，并且与其他探索方法不同，成功的基于结构的药物设计必须考虑到这种灵活性。蛋白质灵活性，SubPEx 将把计算工作集中在结合口袋本身上。源许可证将鼓励采用。我们预计更广泛的社区中的许多人也将使用 SubPEx。设计结合其自身疾病相关目标蛋白的配体。