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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：
10437666
负责人：
Jacob D Durrant
金额：
$ 30.48万
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/10437666
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 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.

项目总结