PDF(Pubmed)
Abstract：
Drug discovery is a crucial part of human healthcare and has dramatically benefited human lifespan and life quality in recent centuries, however, it is usually time- and effort-consuming. Structural biology has been demonstrated as a powerful tool to accelerate drug development. Among different techniques, cryo-electron microscopy (cryo-EM) is emerging as the mainstream of structure determination of biomacromolecules in the past decade and has received increasing attention from the pharmaceutical industry. Although cryo-EM still has limitations in resolution, speed and throughput, a growing number of innovative drugs are being developed with the help of cryo-EM. Here, we aim to provide an overview of how cryo-EM techniques are applied to facilitate drug discovery. The development and typical workflow of cryo-EM technique will be briefly introduced, followed by its specific applications in structure-based drug design, fragment-based drug discovery, proteolysis targeting chimeras, antibody drug development and drug repurposing. Besides cryo-EM, drug discovery innovation usually involves other state-of-the-art techniques such as artificial intelligence (AI), which is increasingly active in diverse areas. The combination of cryo-EM and AI provides an opportunity to minimize limitations of cryo-EM such as automation, throughput and interpretation of medium-resolution maps, and tends to be the new direction of future development of cryo-EM. The rapid development of cryo-EM will make it as an indispensable part of modern drug discovery.
摘要：
药物发现是人类医疗保健的重要组成部分，并且在近几个世纪以来极大地改善了人类的寿命和生活质量。然而,它通常是耗时和费力的。结构生物学已被证明是加速药物开发的强大工具。在不同的技术中，在过去的十年中，低温电子显微镜（cryo-EM）正在成为生物大分子结构确定的主流，并受到制药行业的越来越多的关注。尽管cryo-EM在分辨率方面仍然有局限性，速度和吞吐量，在cryo-EM的帮助下，正在开发越来越多的创新药物。这里,我们旨在概述如何应用低温EM技术来促进药物发现。简要介绍低温EM技术的发展和典型工作流程,其次是其在基于结构的药物设计中的具体应用，基于片段的药物发现，蛋白水解靶向嵌合体，抗体药物开发和药物再利用。除了cryo-EM,药物发现创新通常涉及其他最先进的技术，如人工智能(AI)，在不同领域越来越活跃。cryo-EM和AI的结合提供了一个机会来最大限度地减少cryo-EM的限制，例如自动化，中等分辨率地图的吞吐量和解释，并将成为冷冻EM未来发展的新方向。cryo-EM的快速发展将使其成为现代药物发现中不可或缺的一部分。
