A molecular simulation and machine learning framework for the rational discovery of allosteric modulators of protein function

该项目将专注于开发一种结合分子模拟、信息论和机器学习方法的计算方法，以预测药物样小分子与蛋白质表面不同位置的结合将如何调节蛋白质的生物功能。这种所谓的变构调节剂对解决具有挑战性的药物靶标特别感兴趣。计算方法将应用于结合药物上重要的酶或蛋白质-蛋白质相互作用的化合物。我们特别感兴趣的是描述击中分子的潜力，弱结合剂通常在药物发现活动的早期阶段通过片段筛选识别，发展成为有效的变构调节剂。这项工作将建立在分子动力学模拟和米歇尔实验室最近用来阐明蛋白质的变构效应的自由能计算方法的基础上。common . 2019)，并指导合理的药物设计工作（Chem. 2019）。Sci, 2019)。该项目将与生物制药公司UCB合作开展，并将在其研发基地进行安置。这是开发、验证和应用下一代计算机辅助药物设计软件和方法的一个令人兴奋的机会。在完成学习后，成功的申请人将在分子建模方面获得强大的技术专长，并学会与制药行业密切合作。这将为他或她将来在学术界或工业界的职业生涯做好准备。

This project will focus on developing a computational methodology that combines molecular simulation, information theory and machine learning methods for predicting how the binding of drug-like small molecules to different locations on the surface of a protein will modulate the biological function of the protein. Such so-called allosteric modulators are of particular interest to tackle challenging drug targets. The computational methodology will be applied to compounds binding to pharmaceutically important enzymes or protein-protein interactions. We are particularly interested in characterising the potential of hit molecules, weak binders typically identified at the early stage of a drug discovery campaign by fragment screens, to be developed into potent allosteric modulators. The work will build on molecular dynamics simulation and free energy calculation methodologies the Michel lab has recently used to elucidate allosteric effects in proteins (Chem. Commun. 2019), and to guide rational drug design efforts (Chem. Sci. 2019). The project will be carried out in collaboration with the biopharmaceutical company UCB and involve placements at their R&D site. This is an exciting opportunity to develop, validate and apply next-generation computer-aided drug design software and methodologies. Upon completion of the studentship, the successful applicant will have gained strong technical expertise in molecular modelling and learned to work closely with the pharmaceutical industry sector. This will prepare him or her well for a future career in academia or industry.