Molecular dynamics simulations have become indispensable for exploring complex biological processes, yet their limitations in capturing rare events hinder our understanding of drug–target kinetics. In this Perspective, we investigate the domain of milestoning simulations to understand this challenge. The milestoning approach divides the phase space of the drug–target complex into discrete cells, offering extended time scale insights. This Perspective traces the history, applications, and future potential of milestoning simulations in the context of drug–target kinetics. It explores the fundamental principles of milestoning, highlighting the importance of probabilistic transitions and transition time independence. Markovian milestoning with Voronoi tessellations is revisited to address the traditional milestoning challenges. While observing the advancements in this field, this Perspective also addresses impending challenges in estimating drug–target unbinding rate constants through milestoning simulations, paving the way for more effective drug design strategies.

中文翻译：

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药物靶点动力学的 Milestoning 模拟的进展和挑战


分子动力学模拟已成为探索复杂生物过程不可或缺的一部分，但它们在捕获罕见事件方面的局限性阻碍了我们对药物-靶点动力学的理解。在这个 Perspective 中，我们研究了 milestoning simulation 的领域，以了解这一挑战。英里修正方法将药物-靶标复合物的相空间划分为离散的细胞，从而提供扩展的时间尺度见解。该 Perspective 追溯了在药物靶点动力学背景下 milestoning 模拟的历史、应用和未来潜力。它探讨了 milestoning 的基本原理，强调了概率转换和转换时间独立性的重要性。重新审视了使用 Voronoi 镶嵌的马尔可夫英里调音，以解决传统的调音挑战。在观察该领域的进步的同时，该视角还解决了通过迈尔斯通仿真估计药物-靶标脱结合速率常数的迫在眉睫的挑战，为更有效的药物设计策略铺平了道路。