Improving Rational Drug Design for Membrane Targets with AI and Advanced Simulation

我们的目标是开发新的最先进的工具，这将加速发现非常困难和探索不足的膜蛋白药物靶点的药物。该提案建立在两个合作伙伴之间非常成功的iCASE学生关系的基础上，但将其扩展到新的发现领域。这个项目的时间安排也将允许连续的学生之间的知识转移的最佳重叠。在以前的工作中，我们建立了最先进的结合亲和力计算脂质暴露的结合位点的方法。这项工作开辟了新的领域，目前正在Vertex内部进行评估，以确定如何将其集成到现有的工作流程中。在这个学生项目中，我们希望探索这些工具的发展，以通常作用于膜-蛋白质-水界面的化合物-可能是药物可以作用的最复杂的溶剂环境，迄今为止，这是一个在药物设计方法方面仍处于探索阶段的领域。此外，这一领域特别及时，因为最近有一系列基于cryo-EM革命的出版物，显示已知的药物在双层-水-蛋白质界面环境中相互作用。随着越来越多的结构信息出现（现在AlphaFold的成功也大大补充了这一点），为了优化药物设计过程，研究这些位点的动力学和构象特性将变得至关重要。（见最近关于VX-548 - https的新闻稿：//investors.vrtx.com/news-releases/news-release-details/vertex-announces-nav 18-cardior-advancing-phase-2-clinical），这是该项目的重点。在公共领域和Vertex内部也有大量的数据（结构、药理学、电生理学）。该项目的主要目的是1）表征和理解与精确绝对结合自由能相关的问题这些类型的结合位点的（亲和力）预测2）研究这些计算中的电场效应，3）开发基于AI的方法来加速这一过程的关键要素-无论是计算本身还是预测，而无需昂贵的计算。结果，尽管专注于渠道，但它将广泛适用于许多其他感兴趣的目标（CFTR、运输商等）。新药既是MRC优先研究的领域（先进疗法的新技术），也是Vertex科学愿景的范围。这个协同项目的时机特别合适-NaV通道的最新冷冻EM结构，AI方法的改进（我们已经纳入）和双方合作伙伴在这些领域的最前沿的定位意味着这是一个极好的机会，在一个困难的领域取得重大进展。在整个学生期间，学生将获得执行ABFE计算的关键专业知识，并将开发和应用计算方法，这将增强我们对受体蛋白质内配体结合的构象变化和性质的知识。这些技能属于MRC分子和细胞医学的药理学，结构生物学和生物物理学主题。学生将探索分子和大分子复合物的原子组织，并将探索细胞成分之间的功能关系。在这些方面的发展将使我们能够更好地在分子、细胞和系统水平上模拟药物作用的机制，并有助于提高药物的疗效和靶向性。项目合作伙伴将开展的工作描述，包括联系的性质和频率：鉴于Vertex的邻近性（位于大学以南几英里的米尔顿公园）

We aim to develop new state-of-the-art tools that will accelerate the discovery of medicines for very difficult and under-explored membrane protein drug targets. The proposal builds upon a very successful previous iCASE studentship between the two partners, but will extend it into new areas of discovery. The timing of this project will also allow an optimal overlap of knowledge transfer between successive students.In previous work, we established methodologies for state-of-the-art binding affinity calculations for lipid-exposed binding sites. The work, which breaks new ground, is currently being evaluated within Vertex in terms of how it can be integrated into existing workflows. In this studentship, we wish to explore the development of these tools to compounds that typically act at the membrane-protein-water interface - possibly the most complex solvent environment that a drug can act at, and to date is an area that remains under-explored in terms of drug-design approaches.Furthermore, this area is particularly timely, as there has been a recent slew of publications, based upon the cryo-EM revolution, that have shown known drugs interacting at sites that sit in the bilayer-water-protein interface environment. As more and more structural information appears (now also substantially supplemented by the success of AlphaFold), it will become essential to characterise the dynamics and conformational properties of these sites in order to optimize the drug design process.Systems that are of interest to both Biggin and Vertex, are ion channels (see the recent press release regarding VX-548 - https://investors.vrtx.com/news-releases/news-release-details/vertex-announces-nav18-inhibitor-advancing-phase-2-clinical) and this is where the project will focus., There is also a substantial amount of data (structural, pharmacological, electrophysiological) both in the public domain as well as within Vertex. The key aims of the project are to 1) Characterize and understand the problems associated with making accurate absolute binding free energy (affinity) predictions for these types of binding sites 2) To investigate electric-field effects in these calculations and 3) To develop AI-based approaches to speed up key elements of this process - either the calculations per se or predictions without expensive calculations at all.The results, although focussed on channels will be broadly applicable to many other targets of interest (CFTR, transporters, etc). Novel medicines are both an MRC prioritised area of research (new technologies for advanced therapies) and in the remit of the scientific vision of Vertex. The timing of this synergistic project is particularly appropriate - recent cryo-EM structures of NaV channels, improvements in AI approaches (which we are already incorporating) and the positioning of both partners at the forefront of these areas means that this presents a fantastic opportunity to make significant progress in a difficult field.Throughout the studentship, the student will be gaining key expertise in performing ABFE calculations and will be developing and applying computational methods that will enhance our knowledge of conformational changes and properties of ligand-binding within receptor proteins. These skills fall within the MRC remit of Molecular and cellular medicine under the pharmacology, structural biology and biophysics themes. The student will probe into the atomic organization of molecules and macromolecular complexes and will explore functional relationships between cellular components. Developments on these fronts will enable us to better model the mechanics of drug action at molecular, cellular and systems levels and could help improve the efficacy and targeting of drugs.Description of work to be carried out at project partner, including the nature and frequency of contact:Given the proximity of Vertex (at Milton Park, just a few miles south of the University