走向自动化基于物理的绝对药物停留时间预测
Zachary Smith1, Davide Branduardi2, Dmitry Lupyan3
1Schrödinger, New York, 1540 Broadway, 24th Floor, New York, New York 10036, United States.
Journal of chemical information and modeling
|December 9, 2025
概括
计算药物停留时间对于药物发现至关重要. 结合随机加速分子动力学和不频繁的元动力学的新计算方法准确地预测了药物位的停留时间,有助于配体优化.
科学领域:
- 计算化学和分子动力学
- 药物发现和药物化学
背景情况:
- 药物停留时间 (τ) 是联体优化中的关键参数,影响着超出结合亲和度的化合物概况.
- 准确预测居住时间对于高效的小分子药物发现计划至关重要.
研究的目的:
- 引入一种用于计算绝对药物停留时间的新计算协议.
- 为药物发现提供一种方法,平衡准确性,吞吐量和易用性.
主要方法:
- 一种两相增强采样方法:随机加速分子动力学 (RAMD) 用于路径采集和不频繁的元动力学 (iMetaD) 用于停留时间估计.
- 协议适用于29个药物标复合体,在五个不同的标中,没有手动参数调节.
主要成果:
- 组合RAMD和iMetaD协议在预测居住时间方面取得了良好的准确性.
- 定量指标与实验值有很强的相关性 (RMSE为1.22和R2为0.80在log10(τ)).
结论:
- 这种计算方案提供了一种强大而准确的方法来确定药物停留时间.
- 该协议适用于小分子药物发现,增强连接体优化策略.
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