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循环连接器设计和优化通过分子动力学模拟

Lei Yu¹, Stephanie A Barros¹, Chengzao Sun¹

¹Janssen Research & Development, LLC, Spring House, Pennsylvania 19477, United States.

Journal of chemical information and modeling

|October 30, 2023

概括

我们开发了一种分子动力学模拟方法,以评估链接器修改如何影响循环稳定性. 这种方法有助于设计更强大,更稳定的循环,用于药物发现.

科学领域:

计算化学和分子建模.
药物化学和药物发现
生物物理和结构生物学

背景情况:

循环是有前途的治疗药物,由于其高亲和力和选择性,准蛋白质-蛋白质相互作用.
宏循环是稳定形状和增强药物特性的一个关键策略.
预测宏环化对稳定性和结合性的影响对于药物设计至关重要.

研究的目的:

提出一种新的计算方法,用于评估链接器变异对循环形态稳定性的影响.
为了证明该方法在各种循环结构和蛋白质标 (PCSK9,素,MDM2) 中的适用性.
为了将溶液稳定性与受体结合形状和结合亲和关系相关联.

主要方法:

使用明确溶剂增强采样分子动力学 (MD) 模拟.
多种连接器长度和化学成分,以评估形状稳定性.
将该方法应用于针对PCSK9,素和MDM2.2的三个循环序列.

主要成果:

模拟通常表明,对于高亲和度循环的受体结合形态,溶液稳定性更高.
这一发现支持了这种假设,即连接体的预组织增强了结合亲和力.
研究了力场和采样对特定序列的模拟结果的影响.

结论:

开发的MD模拟方法有效估计了宏环化对稳定性的影响.
这些发现为优化循环的设计提供了洞察力,以提高功效和稳定性.
在内部药物发现计划中成功地应用了这种计算方法,用于设计增强的循环.

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