Fragment-based drug discovery (FBDD) is an innovative approach, progressively more applied in the academic and industrial context, to enhance hit identification for previously considered undruggable biological targets. In particular, FBDD discovers low-molecular-weight (LMW) ligands (<300 Da) able to bind to therapeutically relevant macromolecules in an affinity range from the micromolar (μM) to millimolar (mM). X-ray crystallography (XRC) and nuclear magnetic resonance (NMR) spectroscopy are commonly the methods of choice to obtain 3D information about the bound ligand–protein complex, but this can occasionally be problematic, mainly for early, low-affinity fragments. The recent development of computational fragment-based approaches provides a further strategy for improving the identification of fragment hits. In this review, we summarize the state of the art of molecular dynamics simulations approaches used in FBDD, and discuss limitations and future perspectives for these approaches.

基于片段的药物发现（FBDD）是一种创新方法，逐渐更多地应用于学术和工业领域，以增强对先前认为不可成药的生物靶标的命中识别。特别是，FBDD 发现低分子量 (LMW) 配体 (<300 Da) 能够以微摩尔 (μM) 到毫摩尔 (mM) 的亲和力范围与治疗相关的大分子结合。 X 射线晶体学 (XRC) 和核磁共振 (NMR) 光谱学是获取结合配体-蛋白质复合物 3D 信息的常用方法，但这有时可能会出现问题，主要针对早期的低亲和力片段。基于计算片段的方法的最新发展为改进片段命中的识别提供了进一步的策略。在这篇综述中，我们总结了 FBDD 中使用的分子动力学模拟方法的最新技术，并讨论了这些方法的局限性和未来前景。