Systematic discovery of functional allostery for next generation chemical modulators

变构位点提供了调节蛋白质功能的根本重要机制，由此在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受到高度追捧，因为它们在家族中的保守性通常低于主要位点，并提供了影响其他不可药用活性位点的强大机制。一种用于从头鉴定和验证可药物化的变构分子途径的通用方法将为针对所有疾病领域目前难以治疗的靶点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，以建立第一个高通量平台，用于通用发现，验证和靶向整个蛋白质组的功能变构位点。您将通过生成人类蛋白质翻译的第一个变构调节剂来证明您的多学科方法的概念证明，加深我们对生命规则的理解，以及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，该项目将非常适合具有药物化学或化学生物学研究经验的学生，以及整合这些领域专业知识以创建新药物发现范式的雄心。

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.