Protein-ligand binding affinity prediction of cyclin‐dependent kinase‐2 inhibitors by dynamically averaged fragment molecular orbital‐based interaction energy
Protein-ligand binding affinity prediction of cyclin‐dependent kinase‐2 inhibitors by dynamically averaged fragment molecular orbital‐based interaction energy
复制标题
通过动态平均片段分子轨道相互作用能预测细胞周期蛋白依赖性激酶 2 抑制剂的蛋白质配体结合亲和力
DOI：
10.1002/jcc.26940
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发表时间：
2022
影响因子：
3
通讯作者：
Tanaka Shigenori
中科院分区：
文献类型：
--
作者：
Takaba Kenichiro;Watanabe Chiduru;Tokuhisa Atsushi;Akinaga Yoshinobu;Ma Biao;Kanada Ryo;Araki Mitsugu;Okuno Yasushi;Kawashima Yusuke;Moriwaki Hirotomo;Kawashita Norihito;Honma Teruki;Fukuzawa Kaori;Tanaka Shigenori
片段分子轨道（FMO）方法是基于结构的药物设计的一种强有力的计算工具，其中蛋白质-配体相互作用可以通过片段间相互作用能（IFIE）及其对相互作用能分解分析（PIEDA）来描述。在这里，我们介绍了一种基于动态平均（DA）FMO的方法，其中使用分子动力学模拟来生成用于FMO计算的多个蛋白质-配体复合物结构。为了评估这种方法，我们检查了净电荷为零的六种CDK 2抑制剂的实验结合自由能和DA-IFIE之间的相关性。X射线晶体结构的实验结合自由能和快照IFIE之间的相关性为R2 = 0.75。使用DA‐ IFIE，相关性显著改善至0.99。当加入净电荷为-1的CDK 2抑制剂时，基于DA FMO的方案的色散能仍然为R2 = 0.99，而采用PIEDA的所有能量项时，R2降至0.32。
Fragment molecular orbital (FMO) method is a powerful computational tool for structure‐based drug design, in which protein–ligand interactions can be described by the inter‐fragment interaction energy (IFIE) and its pair interaction energy decomposition analysis (PIEDA). Here, we introduced a dynamically averaged (DA) FMO‐based approach in which molecular dynamics simulations were used to generate multiple protein–ligand complex structures for FMO calculations. To assess this approach, we examined the correlation between the experimental binding free energies and DA‐IFIEs of six CDK2 inhibitors whose net charges are zero. The correlation between the experimental binding free energies and snapshot IFIEs for X‐ray crystal structures wasR2= 0.75. Using the DA‐IFIEs, the correlation significantly improved to 0.99. When an additional CDK2 inhibitor with net charge of −1 was added, the DA FMO‐based scheme with the dispersion energies still achievedR2= 0.99, whereasR2decreased to 0.32 employing all the energy terms of PIEDA.