A virtual reality environment for interactive biomolecular drug discovery

分子模拟是理解和设计生化体系结构不可缺少的工具，因为它在分子尺度上提供了对广泛疾病的微观理解，使我们能够在纳米尺度上设计有针对性的药物来治疗疾病。药物设计问题实际上是“形状匹配”的问题--即设计一种小分子配体(一种药物)，使其贴合到较大的分子受体(蛋白质)中--一种类似于“3D分子俄罗斯方块”的东西。这一设计过程中最大的挑战之一来自这样一个事实：生物分子系统是具有数千个自由度的灵活对象：在药物设计过程中需要考虑大量不同的形状。为了解决这种复杂性，生物分子科学家通常使用以下方法：他们假设生物分子是刚性的，他们使用盲目搜索算法来搜索配体和受体之间可能匹配的高维空间。最近，在人机交互的前沿，分子模拟已经开始研究另一种策略来解决这个搜索问题：交互式分子模拟(IMS)。IMS的思想是，设计良好的人机界面为专家提供了机会，让人类的直觉‘指导’盲目搜索算法，有效地将人类的高级推理能力与现代HPC体系结构的强大计算能力结合在一起。评估iMS工具性能的初步结果表明，它们允许的搜索效率远远高于单独的“盲目搜索”算法。David Glowacki博士的团队一直是IMS平台开发的先锋，最近开发了一个完全交互的分子模拟环境原型，该环境工作在新兴的VR技术类别中，允许实时三维操纵生物分子动态模拟。在这个项目中，博士生海伦·迪克斯将进一步试验和开发这个原型IMS VR环境，并研究如何将其转变为分子纳米级药物设计的有效平台。最初的申请将集中在开发治疗疟疾的药物上，理查德·塞申斯教授(生物化学系)在这一领域拥有丰富的专业知识，并提供了热情的支持。具体地说，海伦的VR开发活动将集中在交互式设计药物分子来抑制乳酸脱氢酶，这是杀死脑型疟疾寄生虫的关键。这个项目的成功实施将受益于一系列学科的专业知识，因此可能会对计算机科学、生物化学和卫生产生广泛的影响。该项目将在人机界面研究界和生物化学研究界产生成果。

Molecular simulation constitutes an indispensable tool in both understanding and designing biochemical archi-tectures.Because it furnishes microscopic understanding into a wide range of diseases at the molecular scale, it ena-bles us to designtargeted pharmaceutical remedies to tackle disease at the nano-scale. Drug design problems are effectively problems of'shape-matching' - i.e., designing a small molecular ligand (a drug) that fits snugly into a larger molecular receptor (a protein) -a sort of "3d molecular Tetris". One of the biggest challenges in this design process arises from the fact that biomolecularsystems are flexible objects with thousands of degrees of freedom: there is a massive range of different shapes to considerduring drug design. To tackle this complexity, biomolecular scientists typically use the following approach: they assume thatbiomolecules are rigid, and they use 'blind-search' algorithms to search the high-dimensional space of possible fits betweenligand and receptor.Recent work at the frontiers of HCI and molecular simulation has begun to investigate another strategy to tackle this searchproblem: interactive molecular simulation (iMS). The idea of iMS is that a well-designed human-computer interface offers theopportunity for expert human intuition to 'guide' blind search algorithms, effectively combining the high-level reasoning abilitiesof humans with the brute force compute power of modern HPC architec-tures. Initial results assessing the performance of iMStools have shown that they allow for much more efficient searching than 'blind-search' algorithms alone. Dr. David Glowacki'sgroup has been at the vanguard of iMS platform development, and has recently developed a prototype for a fully interactivemolecular simulation environment that works in the new class of emerging VR technologies, allowing for real-time 3dmanipulation of biomolecular dynam-ics simulations.In this project, PhD candidate Helen Deeks will experiment with and develop this prototype iMS VR environment further, andinvestigate how to transform it into an effective platform for designing drugs at the molecular nano-scale. The initial applicationwill focus on developing pharmaceutical remedies for malaria, a domain where Prof. Richard Sessions (Dept of Biochemistry)has significant expertise and has offered his enthusiastic support. Specifi-cally, Helen's VR development activities will focus oninteractively designing drug molecules to inhibit the lactate dehydrogenase enzyme, which is key to killing the parasiteresponsible for cerebral malaria. Successful execution of this project will benefit from expertise across a range of disciplines,and thus has potentially wide impact across computer science, biochemistry, and health. This project will lead to outputs inboth the HCI research community and the biochemistry research community.