Mechanism of XiJiaQi in the treatment of chronic heart failure: Integrated analysis by pharmacoinformatics, molecular dynamics simulation, and SPR validation

Dongyang Zhao; Kaijing Guo; Qian Zhang; Yan Wu; Chen Ma; Wenyi He; Xiangju Jin; Xinyu Zhang; Yanan Wang; Sheng Lin; Hongcai Shang

doi:10.1016/j.compbiomed.2023.107479

Mechanism of XiJiaQi in the treatment of chronic heart failure: Integrated analysis by pharmacoinformatics, molecular dynamics simulation, and SPR validation

Comput Biol Med. 2023 Sep 20:166:107479. doi: 10.1016/j.compbiomed.2023.107479. Online ahead of print.

Authors

Dongyang Zhao¹, Kaijing Guo¹, Qian Zhang², Yan Wu¹, Chen Ma¹, Wenyi He¹, Xiangju Jin¹, Xinyu Zhang¹, Yanan Wang³, Sheng Lin⁴, Hongcai Shang⁵

Affiliations

¹ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
² Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China.
³ State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: wangyanan@imm.ac.cn.
⁴ Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China. Electronic address: lsznn@bucm.edu.cn.
⁵ Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China. Electronic address: shanghongcai@126.com.

PMID: 37783074
DOI: 10.1016/j.compbiomed.2023.107479

Abstract

Objective: Chronic heart failure (CHF) is a complicated clinical syndrome with a high mortality rate. XiJiaQi (XJQ) is a traditional Chinese medicine used in the clinical treatment of CHF, but its bioactive components and their modes of action remain unknown. This study was designed to unravel the molecular mechanism of XJQ in the treatment of CHF using multiple computer-assisted and experimental methods.

Methods: Pharmacoinformatics-based methods were used to explore the active components and targets of XJQ in the treatment of CHF. ADMETlab was then utilized to evaluate the pharmacokinetic and toxicological properties of core components. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were to explore the underlying mechanism of XJQ treatment. Molecular docking, surface plasmon resonance (SPR), and molecular dynamics (MD) were employed to evaluate the binding of active components to putative targets.

Results: Astragaloside IV, formononetin, kirenol, darutoside, periplocin and periplocymarin were identified as core XJQ-related components, and IL6 and STAT3 were identified as core XJQ targets. ADME/T results indicated that periplocin and periplocymarin may have potential toxicity. GO and KEGG pathway analyses revealed that XJQ mainly intervenes in inflammation, apoptosis, diabetes, and atherosclerosis-related biological pathways. Molecular docking and SPR revealed that formononetin had a high affinity with IL6 and STAT3. Furthermore, MD simulation confirmed that formononetin could firmly bind to the site 2 region of IL6 and the DNA binding domain of STAT3.

Conclusion: This study provides a mechanistic rationale for the clinical application of XJQ. Modulation of STAT3 and IL-6 by XJQ can impact CHF, further guiding research efforts into the molecular underpinnings of CHF.

Keywords: Chronic heart failure; Molecular docking; Molecular dynamics simulation; Pharmacoinformatics; Surface plasmon resonance; Traditional Chinese medicine; XiJiaQi formula.