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Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation

文献类型：期刊论文

作者Feng, Dazhi4,5,6; Liu, Bo3; Chen, Zhiwei2,4; Xu, Jinyi5,6; Geng, Meiyu1,2,3; Duan, Wenhu1,2,4; Ai, Jing2,3; Zhang, Hefeng4
刊名JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
出版日期2024-01-03
页码13
关键词HPK1 inhibitor machine learning virtual screening free energy perturbation structural modification
ISSN号0739-1102
DOI10.1080/07391102.2024.2301754
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Hefeng(zhanghefeng1@simm.ac.cn)
英文摘要Hematopoietic progenitor kinase 1 (HPK1) is a key negative regulator of T-cell receptor (TCR) signaling and a promising target for cancer immunotherapy. The development of novel HPK1 inhibitors is challenging yet promising. In this study, we used a combination of machine learning (ML)-based virtual screening and free energy perturbation (FEP) calculations to identify novel HPK1 inhibitors. ML-based screening yielded 10 potent HPK1 inhibitors (IC50 < 1 mu M). The FEP-guided modification of the in-house false-positive hit, DW21302, revealed that a single key atom change could trigger activity cliffs. The resulting DW21302-A was a potent HPK1 inhibitor (IC50 = 2.1 nM) and potently inhibited cellular HPK1 signaling and enhanced T-cell function. Molecular dynamics (MD) simulations and ADME predictions confirmed DW21302-A as candidate compound. This study provides new strategies and chemical scaffolds for HPK1 inhibitor development.
WOS关键词PHASE-I ; HPK1 ; IMMUNOTHERAPY ; IMMUNOLOGY ; PREDICTION
资助项目Natural Science Foundation of China for Innovation Research Group
WOS研究方向Biochemistry & Molecular Biology ; Biophysics
语种英语
WOS记录号WOS:001140976900001
出版者TAYLOR & FRANCIS INC
源URL[http://119.78.100.183/handle/2S10ELR8/308648]  
专题新药研究国家重点实验室
通讯作者Ai, Jing; Zhang, Hefeng
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Shandong, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Div Antitumor Pharmacol, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
5.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Peoples R China
6.China Pharmaceut Univ, Dept Med Chem, Nanjing, Peoples R China
推荐引用方式
GB/T 7714		 Feng, Dazhi,Liu, Bo,Chen, Zhiwei,et al. Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation[J]. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,2024:13.
APA Feng, Dazhi.,Liu, Bo.,Chen, Zhiwei.,Xu, Jinyi.,Geng, Meiyu.,...&Zhang, Hefeng.(2024).Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation.JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS,13.
MLA Feng, Dazhi,et al."Discovery of hematopoietic progenitor kinase 1 inhibitors using machine learning-based screening and free energy perturbation".JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS (2024):13.

入库方式： OAI收割

来源：上海药物研究所

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