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基于碎片分子轨道方法的结合性自由能量计算及其在设计新型SHP-2体抑制剂中的应用

Zhen Yuan¹, Xingyu Chen¹, Sisi Fan¹

¹Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China.

International journal of molecular sciences

|January 11, 2024

概括

一种新的量子力学方法,FMOScore,通过包括溶解和变形能量,准确地预测结合的自由能量. 这种方法通过改善联体蛋白结合亲和性预测来增强药物设计,并导致发现了一种新型SHP-2抑制剂.

科学领域:

计算化学是一种计算化学.
药物发现药物发现
结构生物学是结构生物学.

背景情况:

准确预测结合的自由能量对于基于结构的药物设计至关重要.
量子力学 (QM) 方法提供了高精度,但面临着计算方面的挑战.
碎片分子轨道 (FMO) 方法降低了QM计算成本,但需要用于结合亲和力预测的增强.

研究的目的:

开发一种改进的基于QM的方法,用于预测连接物-蛋白结合的自由能量.
通过结合额外的能量项来增强碎片分子轨道 (FMO) 方法.
为了验证新方法的性能与既有预测技术相比.

主要方法:

开发了FMOScore,一种基于QM的具有约束力的自由能量计算方法.
将气相潜在能量,变形能量和溶解自由能量纳入线性合适模型中.
评估隐式溶剂方法以提高FMO性能.
将FMOScore预测与FEP+,MM/PBSA,MM/GBSA和Autodock vina进行了比较.

主要成果:

与传统方法相比,FMOScore显示出良好的预测准确度.
包括溶解自由能量和变形能量计算在内,提高了FMO对结合亲和力的精度.
一个回顾性案例研究证实了增强的预测能力.
在FMOScore指导的优化中,发现了一种新且强效的全性SHP-2抑制剂 (化合物8).

结论:

在药物设计中,FMOScore提供了一个更准确和计算可行的方法来预测结合的自由能量.
纳入溶解和变形能量对于改进基于QM的结合亲和力预测至关重要.
开发的方法有助于有效的药物发现,正如新的SHP-2抑制剂的识别所证明的那样.

关键词:

在 SHP2 中, SHP2 是 SHP2.有约束力的自由能源.分片分子轨道方法分子轨道方法.

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