Free energy perturbation (FEP)-guided scaffold hopping.
Free energy perturbation (FEP)-guided scaffold hopping.
复制标题
自由能扰动 (FEP) 引导支架跳跃
DOI：
10.1016/j.apsb.2021.09.027
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发表时间：
2022-03
影响因子：
14.5
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Wu, Deyan;Zheng, Xuehua;Liu, Runduo;Li, Zhe;Jiang, Zan;Zhou, Qian;Huang, Yue;Wu, Xu-Nian;Zhang, Chen;Huang, Yi-You;Luo, Hai-Bin
关键词：
骨架跳跃（Scaffold hopping）是指利用计算机辅助筛选具有不同结构的活性化合物，以丰富具有特殊结构的骨架，是有机化学和药物化学领域的一个热点。然而，大多数方法不能有效地预测支架跳跃后候选物的效力水平。在此，我们通过自由能微扰（FEP）引导的支架跳跃策略鉴定了具有新型支架的有效PDE 5抑制剂，并且FEP显示出精确预测配体与其靶标之间的理论结合效力ΔGFEP的巨大优势，这与实验结合效力ΔGEXP更一致（平均绝对偏差< 2 kcal/mol），而用MM-PBSA或MM-GBSA方法预测的ΔGMM-PBSA或ΔGMM-GBSA的平均绝对偏差小于2 kcal/mol。铅L12的IC 50为8.7 nmol/L，其晶体结构与著名起始药物他达拉非的PDE 5具有不同的结合模式。我们的工作提供了第一份报告，通过FEP引导的支架跳跃策略，有效的抑制剂发现与一种新的支架，这意味着它将有各种未来的应用在合理的分子设计和药物发现。我们的工作提供了关于自由能微扰（FEP）引导的支架跳跃策略的第一份报告（|ΔGFEP-ΔGEXP| < 2 kcal/mol），以发现具有新型支架的有效抑制剂。
Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies ΔGFEP between ligands and their target, which were more consistent with the experimental binding potencies ΔGEXP (the mean absolute deviations < 2 kcal/mol) than those ΔGMM-PBSA or ΔGMM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery. Our work provides the first report about the free energy perturbation (FEP)-guided scaffold hopping strategy (|ΔGFEP–ΔGEXP|< 2 kcal/mol) to discover potent inhibitors with a novel scaffold.
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