Systematic discovery of functional allostery for next generation chemical modulators

变构位点为调节蛋白质功能提供了一种基本的重要机制，通过在一个遥远的变构位点上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的药物发现部位而备受追捧，因为它们在家族中通常不像主要部位那样高度保守，并提供了一种强大的机制来影响原本无法用药的活性部位。对于可药物变构分子通路的从头识别和验证的一般方法将为针对所有疾病领域目前难以解决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，您将集成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，用于在整个蛋白质组中普遍发现、验证和定位功能变构位点。你将通过产生第一个人类蛋白质翻译的变构调节剂，加深我们对管理功能变构的生命规则的理解，以及支持抗癌和抗病毒治疗的新方法，来展示你的多学科方法的概念证明。通过我们的实验室，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，这个项目非常适合有药物化学或化学生物学研究经验的学生，并有雄心整合这些领域的专业知识，以创建新的药物发现范例。

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.