Binding/unbinding kinetics are key determinants of drug potencies. However, there are still a lot of challenges in predicting kinetic properties during early-stage drug development. In this work, position-restrained molecular dynamics simulations combined with energy decomposition were applied to extract protein–ligand interaction (PLI) fingerprints along the unbinding pathway of 20 p38 mitogen-activated protein kinase (p38 MAPK) Type II inhibitors. The results showed that the electrostatic and/or van der Waals interaction fingerprints at three key positions can be used for accurate prediction of the dissociation rate constants (k_off) of p38 MAPK Type II inhibitors. The strategy proposed in this paper can provide not only an efficient method of predicting the dissociation rates of the p38 MAPK Type II inhibitors, but also the atom-level mechanism of enthalpy-driven unbinding process.

中文翻译：

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蛋白质-配体相互作用指纹，用于准确预测 p38 MAPK II 型抑制剂的解离速率


结合/解开动力学是药物效力的关键决定因素。然而，在早期药物开发过程中预测动力学特性仍然存在很多挑战。在这项工作中，应用位置限制的分子动力学模拟与能量分解相结合，沿着 20 个 p38 丝裂原激活蛋白激酶 (p38 MAPK) II 型抑制剂的解结合途径提取蛋白质-配体相互作用 (PLI) 指纹。结果表明，三个关键位置的静电和/或范德华相互作用指纹可用于准确预测p38 MAPK II型抑制剂的解离速率常数( k _off )。本文提出的策略不仅可以提供预测p38 MAPK II型抑制剂解离速率的有效方法，而且可以提供焓驱动解结合过程的原子级机制。