Novel inhibitors of the (VIBVN) NAT protein identified through pharmacophore modeling

Wei Wei; Xionghao Li; Ning Hou; Aowei Xie; Huicong Liang; Ting Gao; Xiaoli Jing; Liqin Li; Jiejie Hao; Ximing Xu

doi:10.1038/s41598-025-85869-4

Novel inhibitors of the (VIBVN) NAT protein identified through pharmacophore modeling

Sci Rep. 2025 Jan 23;15(1):2898. doi: 10.1038/s41598-025-85869-4.

Authors

Wei Wei^#^{1

2}, Xionghao Li^#^{3

2

4}, Ning Hou³, Aowei Xie⁵, Huicong Liang³, Ting Gao⁵, Xiaoli Jing⁴, Liqin Li^{1

6}, Jiejie Hao³, Ximing Xu^{7

8

9}

Affiliations

¹ Affiliated Huzhou Hospital, The Key Laboratory of Molecular Medicine, Zhejiang University School of Medicine, Huzhou Central Hospital, The Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, 313000, China.
² Marine Biomedical Research Institute of Qingdao, Qingdao, 266071, China.
³ Key Laboratory of Marine Drugs, School of Medicine and Pharmacy, Ministry of Education, Ocean University of China, Qingdao, 266071, China.
⁴ Network and Information Center, Qingdao Marine Science and Technology Center, Qingdao, 266237, China.
⁵ College of Food Science and Engineering, Ocean University of China, Qingdao, 266071, China.
⁶ TCM Key Laboratory Cultivation Base of Zhe jiang Province for the Development and Clinical Transformation of Immunomodulatory drugs, Huzhou Central Hospital, Huzhou, 313000, China.
⁷ Key Laboratory of Marine Drugs, School of Medicine and Pharmacy, Ministry of Education, Ocean University of China, Qingdao, 266071, China. xuximing@ouc.edu.cn.
⁸ Marine Biomedical Research Institute of Qingdao, Qingdao, 266071, China. xuximing@ouc.edu.cn.
⁹ Network and Information Center, Qingdao Marine Science and Technology Center, Qingdao, 266237, China. xuximing@ouc.edu.cn.

^# Contributed equally.

PMID: 39843504
DOI: 10.1038/s41598-025-85869-4

Abstract

Arylamine N-acetyltransferases (NATs, E.C. 2.3.1.5) constitute a family of phase II drug metabolizing enzymes. These enzymes catalyze the transfer of acetyl groups from acetyl-CoA to a variety of substrates including arylamines, arylhydrazines, and N-hydroxyarylamines. By facilitating these reactions, NATs play a pivotal role in the detoxification and metabolic processing of a wide range of drugs and carcinogens. NAT in marine V. vulnificus plays a role in the metabolism of drugs, leading to the development of drug resistance in marine V. vulnificus. However, inhibitors targeted marine V. vulnificus NAT [(VIBVN)NAT] remain unclear. Therefore, our research aimed to identify potential hit compounds that target (VIBVN)NAT. We integrated multiple computational approaches to screen for effective inhibitors. From this process, we identified two hit compounds, AK-968-11563024 and AG-205-36710025, with IC₅₀ values of 18.86 µM and 33.27 µM, respectively. Molecular dynamics simulations further elucidated the binding mechanism between (VIBVN)NAT and AK-968-11563024. Our study revealed that AK-968-11563024 forms stable interactions with PHE124, HIS167, and TRP230, which may contribute to its biological activity. Our findings provide a valuable foundation for the future development of drugs targeted therapeutics against (VIBVN)NAT.

MeSH terms

Arylamine N-Acetyltransferase* / antagonists & inhibitors
Arylamine N-Acetyltransferase* / chemistry
Arylamine N-Acetyltransferase* / metabolism
Enzyme Inhibitors* / chemistry
Enzyme Inhibitors* / pharmacology
Molecular Docking Simulation
Molecular Dynamics Simulation*
Pharmacophore
Protein Binding

Substances

Arylamine N-Acetyltransferase
Enzyme Inhibitors

Abstract

MeSH terms

Substances

Grants and funding