Original articles
Deyan Wu, Xuehua Zheng, Runduo Liu, Zhe Li, Zan Jiang, Qian Zhou, Yue Huang, Xu-Nian Wu, Chen Zhang, Yi-You Huang, Hai-Bin Luo. Free energy perturbation (FEP)-guided scaffold hopping[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1351-1362

Free energy perturbation (FEP)-guided scaffold hopping
Deyan Wua,b, Xuehua Zhengc, Runduo Liub, Zhe Lib, Zan Jiangc, Qian Zhoub, Yue Huangb, Xu-Nian Wub, Chen Zhangb, Yi-You Huanga,b, Hai-Bin Luoa,b
a. School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China;
b. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China;
c. School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China
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 |ΔGFEPGEXP|< 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.
Key words:    Free energy perturbation    Scaffold hopping    Privileged scaffolds    Drug discovery    Binding potencies    Molecular design    PDE5 inhibitors    Pulmonary arterial hypertension   
Received: 2021-07-15     Revised: 2021-09-03
DOI: 10.1016/j.apsb.2021.09.027
Funds: This work was supported by Natural Science Foundation of China (21877134, 81872727, 22077143, 21702238, 82003576, and 81703341), Guangzhou Science and Technology Project (The People's Livelihood Programs for Science and Technology, 201803010075, China), Science Foundation of Guangzhou City (201904020023, China), and Fundamental Research Funds for Hainan University (KYQD(ZR)-21031, China).
Corresponding author: Yi-You Huang,E-mai:huangyy287@mail.sysu.edu.cn;Hai-Bin Luo,E-mai:luohb77@mail.sysu.edu.cn     Email:huangyy287@mail.sysu.edu.cn;luohb77@mail.sysu.edu.cn
Author description:
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Deyan Wu
Xuehua Zheng
Runduo Liu
Zhe Li
Zan Jiang
Qian Zhou
Yue Huang
Xu-Nian Wu
Chen Zhang
Yi-You Huang
Hai-Bin Luo

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