Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Salah Abdulrazak Alshehade; Raghdaa Hamdan Al Zarzour; Vikneswaran Murugaiyah; Sharoen Yu Ming Lim; Huda Ghaleb El-Refae; Mohammed Abdullah Alshawsh

doi:10.1016/j.jsps.2022.09.001

Mechanism of action of Orthosiphon stamineus against non-alcoholic fatty liver disease: Insights from systems pharmacology and molecular docking approaches

Saudi Pharm J. 2022 Nov;30(11):1572-1588. doi: 10.1016/j.jsps.2022.09.001. Epub 2022 Sep 14.

Authors

Salah Abdulrazak Alshehade^{1

2}, Raghdaa Hamdan Al Zarzour^{1

3}, Vikneswaran Murugaiyah¹, Sharoen Yu Ming Lim⁴, Huda Ghaleb El-Refae⁵, Mohammed Abdullah Alshawsh²

Affiliations

¹ Department of Pharmacology, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang 11800, Malaysia.
² Department of Pharmacology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia.
³ Department of Pharmacology, Faculty of Pharmacy, Arab International University (AIU), Damascus, Syria.
⁴ Division of Biomedical Sciences, School of Pharmacy, University of Nottingham Malaysia, Semenyih 43500, Malaysia.
⁵ College of Pharmacy, Al Ain University, Al Ain 64141, United Arab Emirates.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common complications of a metabolic syndrome caused by excessive accumulation of fat in the liver. Orthosiphon stamineus also known as Orthosiphon aristatus is a medicinal plant with possible potential beneficial effects on various metabolic disorders. This study aims to investigate the in vitro inhibitory effects of O. stamineus on hepatic fat accumulation and to further use the computational systems pharmacology approach to identify the pharmacokinetic properties of the bioactive compounds of O. stamineus and to predict their molecular mechanisms against NAFLD.

Methods: The effects of an ethanolic extract of O. stamineus leaves on cytotoxicity, fat accumulation and antioxidant activity were assessed using HepG2 cells. The bioactive compounds of O. stamineus were identified using LC/MS and two bioinformatics databases, namely the Traditional Chinese Medicine Integrated Database (TCMID) and the Bioinformatics Analysis Tool for the Molecular Mechanism of Traditional Chinese Medicine (BATMAN-TCM). Pathway enrichment analysis was performed on the predicted targets of the bioactive compounds to provide a systematic overview of the molecular mechanism of action, while molecular docking was used to validate the predicted targets.

Results: A total of 27 bioactive compounds corresponding to 50 potential NAFLD-related targets were identified. O. stamineus exerts its anti-NAFLD effects by modulating a variety of cellular processes, including oxidative stress, mitochondrial β-oxidation, inflammatory signalling pathways, insulin signalling, and fatty acid homeostasis pathways. O. stamineus is significantly targeting many oxidative stress regulators, including JNK, mammalian target of rapamycin (mTOR), NFKB1, PPAR, and AKT1. Molecular docking analysis confirmed the expected high affinity for the potential targets, while the in vitro assay indicates the ability of O. stamineus to inhibit hepatic fat accumulation.

Conclusion: Using the computational systems pharmacology approach, the potentially beneficial effect of O. stamineus in NAFLD was indicated through the combination of multiple compounds, multiple targets, and multicellular components.

Keywords: Cellular target; Inflammation; Medicinal plant; Molecular docking; Non-alcoholic fatty liver disease; Orthosiphon aristatus; Orthosiphon stamineus; Oxidative stress; Pathway enrichment analysis; Protein–protein interaction; Systems pharmacology.