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：
10727033
负责人：
Jacob D Durrant
金额：
$ 6.91万
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/10727033
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 Crystallography Data Development Disease Drug Design Drug Targeting Drug resistance FRAP1 gene Growth Influenza Lead Licensing Ligand Binding Ligands Malignant Neoplasms Messenger RNA Methods Molecular Molecular Conformation Motion Neuraminidase Pathway interactions Pharmaceutical Preparations Phosphorylation Predisposition Production Protein Biosynthesis Proteins Publishing RNA Binding Research Resolution Ribosomal Proteins Ribosomes Sampling Shapes Signal Transduction Structure Testing Therapeutic Transcript Translational Repression Translations Validation Work X-Ray Crystallography anti-cancer beta-Lactamase cell growth design drug discovery experimental study flexibility improved in silico inhibitor innovation interest mRNA Translation molecular dynamics novel novel therapeutics open source permissiveness pharmacologic 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.

项目摘要该项目将研究与LA相关的蛋白1（LARP1），这是一种分子开关，允许细胞快速增加蛋白质合成。 LARP1存储并保护制造核糖体蛋白所需的mRNA分子。在雷帕霉素复合物1（MTORC1）的哺乳动物靶标（MTORC1）的反应 LARP1释放其绑定的mRNA。核糖体生产激增，导致蛋白质迅速增加一般合成。我们强大的初步数据使我们提出了两个中心假设。首先，我们假设Larp1- 结合分子（配体）将干扰LARP1 mRNA储存机制，从而降低蛋白质合成。其次，我们假设更好地了解分子结合蛋白的灵活性口袋 - 包括LARP1口袋 - 将改善理性配体设计。我们将在两个中检验这些假设目标。 AIM 1将创建一种新的以口袋为中心的方法，用于模拟蛋白质，称为Subpex。我们将证明传票可以有效揭示两个特征良好的动态口袋的灵活性（来自TEM-1 B- AIM 2将使用低音，虚拟筛选和生物物理实验以识别结合柔性LARP1口袋的新配体。这项工作在几种方面都很重要。 LARP1配体将用作基本科学工具（化学问题）促进我们对LARP1生物学的理解。此外，癌症需要广泛的蛋白质合成，因此破坏MTORC1-LARP1信号传导的分子将作为铅，以进一步发展新的疗法。大多数MTORC1-Pathway抑制剂结合MTOR本身。它们受到阻力突变和/或不完全抑制。 LARP1抑制作用将提供独特而创新的药物方法。传票本身也将具有影响力。许多蛋白质药物靶标具有高灵活的结合口袋，并且成功的基于结构的药物设计必须考虑到这种灵活性。与其他探索方法不同蛋白质的灵活性，子播放将把计算工作集中在装订袋本身上。它的允许，开放 - 源许可将鼓励采用。我们希望更广泛的社区中的许多人也将使用传票设计结合自己感兴趣的疾病蛋白质的配体。