Systematic discovery of functional allostery for next generation chemical modulators

系统发现下一代化学调节剂的功能变构

• 批准号: 2886753
• 金额: --
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2886753
• 关键词: Systematic; discovery; functional; allostery; next

Allosteric sites provide a fundamentally important mechanism for regulation of protein function, whereby molecular interactions at a remote allosteric site trigger changes in activity at the primary site of protein function - for example an enzyme active site or protein interaction interface. They are highly sought after as sites for selective and unique drug discovery as they are generally less highly conserved across families than the primary site and offer a powerful mechanism to influence otherwise undruggable active sites. A general approach for de novo identification and validation of druggable allosteric molecular pathways would offer game-changing potential for drug discovery against currently intractable targets across all areas of disease. In this project you will integrate a suite of emerging computational and experimental technologies from our labs to establish the first high-throughput platform for universal discovery, validation, and targeting of functional allosteric sites across the proteome. You will demonstrate proof of concept for your multidisciplinary approach through generation of the first allosteric modulators of human protein translation, deepening our understanding of the rules of life governing functional allostery, as well as underpinning new approaches to anticancer and antiviral therapeutics. Working across our labs, you will learn and apply new skills and technologies including covalent ligand screening and medicinal chemistry optimisation, in silico modelling and machine learning, CRISPR-Cas gene editing, and molecular cell biology. This project would therefore ideally suit a student with research experience in medicinal chemistry or chemical biology and the ambition to integrate expertise across these areas to create a new drug discovery paradigm.

变构位点为蛋白质功能的调节提供了一种根本上重要的机制，其中远程变构位点的分子相互作用触发蛋白质功能的主要位点（例如酶活性位点或蛋白质相互作用界面）的活性变化。它们作为选择性和独特药物发现的位点而受到高度追捧，因为它们在家族中的保守性通常不如主要位点高，并且提供了强大的机制来影响其他不可成药的活性位点。可药物变构分子途径的从头识别和验证的通用方法将为针对所有疾病领域目前棘手靶标的药物发现提供改变游戏规则的潜力。在这个项目中，您将整合我们实验室的一套新兴计算和实验技术，建立第一个高通量平台，用于跨蛋白质组功能变构位点的通用发现、验证和靶向。您将通过生成第一个人类蛋白质翻译变构调节剂来证明您的多学科方法的概念验证，加深我们对控制功能变构的生命规则的理解，并支持抗癌和抗病毒治疗的新方法。在我们的实验室工作，您将学习和应用新的技能和技术，包括共价配体筛选和药物化学优化、计算机建模和机器学习、CRISPR-Cas 基因编辑和分子细胞生物学。因此，该项目非常适合具有药物化学或化学生物学研究经验并有志于整合这些领域的专业知识以创建新的药物发现范式的学生。