Discovery of selective HDAC6 inhibitors driven by artificial intelligence and molecular dynamics simulation approaches.
10.1016/j.jpha.2025.101338
- Author:
Xingang LIU
1
;
Hao YANG
2
;
Xinyu LIU
2
;
Minjie MOU
3
;
Jie LIU
2
;
Wenying YAN
4
;
Tianle NIU
1
;
Ziyang ZHANG
5
;
He SHI
1
;
Xiangdong SU
6
;
Xuedong LI
2
;
Yang ZHANG
2
;
Qingzhong JIA
1
Author Information
1. Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050017, China.
2. School of Pharmacy, Hebei Medical University, Shijiazhuang, 050017, China.
3. College of Pharmaceutical Sciences, The Second Affiliated Hospital, Zhejiang University School of Medicine, National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
4. Department of Clinical Pharmacy, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
5. Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, 518055, China.
6. Taibidi Pharmaceutical Technology (Shijiazhuang) Co. Ltd, Shijiazhuang, 050000, China.
- Publication Type:Journal Article
- Keywords:
Artificial intelligence;
Compound-protein interaction;
Molecular dynamic simulation;
Selective HDAC6 inhibitor;
Virtual screening
- From:
Journal of Pharmaceutical Analysis
2025;15(8):101338-101338
- CountryChina
- Language:English
-
Abstract:
Increasing evidence showed that histone deacetylase 6 (HDAC6) dysfunction is directly associated with the onset and progression of various diseases, especially cancers, making the development of HDAC6-targeted anti-tumor agents a research hotspot. In this study, artificial intelligence (AI) technology and molecular simulation strategies were fully integrated to construct an efficient and precise drug screening pipeline, which combined Voting strategy based on compound-protein interaction (CPI) prediction models, cascade molecular docking, and molecular dynamic (MD) simulations. The biological potential of the screened compounds was further evaluated through enzymatic and cellular activity assays. Among the identified compounds, Cmpd.18 exhibited more potent HDAC6 enzyme inhibitory activity (IC50 = 5.41 nM) than that of tubastatin A (TubA) (IC50 = 15.11 nM), along with a favorable subtype selectivity profile (selectivity index ≈ 117.23 for HDAC1), which was further verified by the Western blot analysis. Additionally, Cmpd.18 induced G2/M phase arrest and promoted apoptosis in HCT-116 cells, exerting desirable antiproliferative activity (IC50 = 2.59 μM). Furthermore, based on long-term MD simulation trajectory, the key residues facilitating Cmpd.18's binding were identified by decomposition free energy analysis, thereby elucidating its binding mechanism. Moreover, the representative conformation analysis also indicated that Cmpd.18 could stably bind to the active pocket in an effective conformation, thus demonstrating the potential for in-depth research of the 2-(2-phenoxyethyl)pyridazin-3(2H)-one scaffold.
