In-silico discovery of the hapten-based interaction between idiosyncratic hepatotoxic ingredients of Polygonum multiflorum and HLA-B*35:01
10.1097/st9.0000000000000063
- Author:
Dake XIAO
1
;
Xu ZHAO
2
;
Xiaoyan ZHAN
2
;
Zhuo SHI
2
;
Zhaofang BAI
2
;
Jiang ZHENG
3
;
Xiaohe XIAO
2
;
Jiabo WANG
4
Author Information
1. College of Traditional Chinese Medicine, Capital Medical University, Beijing, China; China Military Institute of Chinese Materia, the Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China; Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
2. China Military Institute of Chinese Materia, the Fifth Medical Centre of Chinese PLA General Hospital, Beijing, China; Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
3. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, China
4. College of Traditional Chinese Medicine, Capital Medical University, Beijing, China
- Publication Type:Journal Article
- Keywords:
Idiosyncratic drug-induced liver injury;
Polygonum multiflorum;
Chinese herbal medicine;
Emodin-8-O-β-D-glucoside;
Molecular docking;
molecular dynamics
- From:
Science of Traditional Chinese Medicine
2025;3(1):15-27
- CountryChina
- Language:English
-
Abstract:
Background: The previous research has confirmed the existence of idiosyncratic drug-induced liver injury (IDILI) caused by Polygonum multiflorum (PM-IDILI), and demonstrated that PM-IDILI is an immune-mediated injury, with HLA-B*35:01 identified as a genetic susceptibility marker. Additionally, emodin-8-O-β-D-glucoside (EG) and 2, 3, 5, 4′-tetrahyd roxystilbene-2-O-β-D-glucoside have been proposed as potential contributory ingredients in the pathogenesis of PM-IDILI. However, the precise mechanisms through which these susceptible factors contribute to the development of PM-IDILI remain unclear. Objectives: This study aims to explore the molecular characteristics of HLA-B*35:01 that contribute to PM-DILI and to propose a mechanistic hypothesis based on our previous research on PM-induced protein adducts. Methods: Key differences between HLA-B*35:01 and general Chinese HLA-B alleles were identified by comparing protein sequences, peptide binding motifs, and protein structures. Molecular docking was employed to assess whether PM-induced haptenated peptides can be presented by HLA-B*35:01 and other related alleles. Additionally, a simplified dipeptide model was used to evaluate the binding affinity of HLA-B*35:01 to EG-haptenated peptides. Results: Our findings revealed significant differences in the residues of the B and F peptide binding pockets of HLA-B*35:01 compared to general Chinese HLA-B alleles. Further analysis suggested that the F pocket of HLA-B*35:01 was capable of binding EG-cysteine adducts and might be a key feature in the PM-IDILI pathogenesis. Peptide docking using DINC and molecular dynamics simulations indicated that HLA-B*35:01 could form stable complexes with EG-haptenated peptides. Molecular dynamics simulations also highlighted the critical roles of both the B and F pockets in peptide binding. Specifically, the F pocket binds the EG-modified residue in haptenated peptides, while the B pocket, despite lacking shared features among PM-IDILI patients, may indirectly influence the incidence of PM-IDILI by filtering haptenated peptides. The binding affinity of HLA-B*35:01 to EG-modified cysteine residues was experimentally validated through a dipeptide-based assay, confirming that HLA-B*35:01 could bind EG-haptenated peptides. Conclusions: This study identified the unique B and F binding pockets of HLA-B*35:01 as key factors in PM-IDILI pathogenesis and demonstrated that HLA-B*35:01 could bind EG-haptenated peptides. These findings suggest that PM-IDILI may be a hapten-based drug hypersensitivity reaction driven by EG, providing a theoretical framework for further research aimed at elucidating the molecular mechanisms underlying PM-IDILI.
