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对KRAS^G12D抑制剂结合的机械洞察力,通过多个晶体结构的分子动力学模拟揭示了这一点

Donghwan Kim¹, Eunho Lee¹, Sangbae Lee¹

¹Atomatrix, 851, Daewangpangyo-ro 815, Sujeong-gu, Seongnam-si, Gyeonggi-do, Republic of Korea. sblee@atomatrix.co.kr.

Physical chemistry chemical physics : PCCP

|December 15, 2025

概括

开发强大的KRAS^G12D抑制剂对于癌症治疗至关重要. 分子动力学模拟揭示了关键的结构和动态因素,包括特定的极性相互作用和结合口袋稳定性,这些因素区分了高亲和度KRAS^G12D抑制剂和低亲和度的抑制剂.

科学领域:

在瘤学瘤学.
计算化学计算化学
结构生物学结构生物学

背景情况:

向KRAS^G12D是癌症药物开发中的一个重大挑战.
对于有效的癌症治疗,迫切需要选择性和强大的KRAS^G12D抑制剂.

研究的目的:

阐明区分高和低亲和度KRAS^G12D抑制物的结构和动态因素.
为设计下一代KRAS^G12D抑制剂提供定量见解.

主要方法:

对四种KRAS^G12D-抑制剂复合物的全原子分子动力学 (MD) 模拟进行比较.
结晶学数据与MD模拟的整合.
炼化自由能量计算和每残留能量分解.

主要成果:

计算的自由能量与实验的pIC值之间有很强的相关性 (R² = 0.92).
确定了五个主要的极相互作用热点 (D12,G60,E62,D69,D92),这些热点对于稳定结合至关重要.
强结合剂表现出紧,稳定的结合口袋 (RMSD: 1.8-2.2 Å) 和降低了连接体灵活性,与弱结合剂 (RMSD: 2.7-3.4 Å) 不同.

结论:

特定的极性相互作用和结合口袋动态是KRAS^G12D抑制剂功效的关键决定因素.
这些发现为改进的KRAS^G12D抑制剂的合理设计提供了定量指南.
这项研究通过在分子层面上了解抑制剂-标相互作用,推动了向癌症治疗的发展.

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