In Vitro, In Silico and Network Pharmacology Mechanistic Approach to Investigate the α-Glucosidase Inhibitors Identified by Q-ToF-LCMS from Phaleria macrocarpa Fruit Subcritical CO2 Extract

Md Abdur Rashid Mia; Qamar Uddin Ahmed; Sahena Ferdosh; Abul Bashar Mohammed Helaluddin; Md Shihabul Awal; Murni Nazira Sarian; Md Zaidul Islam Sarker; Zainul Amiruddin Zakaria

doi:10.3390/metabo12121267

In Vitro, In Silico and Network Pharmacology Mechanistic Approach to Investigate the α-Glucosidase Inhibitors Identified by Q-ToF-LCMS from Phaleria macrocarpa Fruit Subcritical CO₂ Extract

Metabolites. 2022 Dec 15;12(12):1267. doi: 10.3390/metabo12121267.

Authors

Md Abdur Rashid Mia¹, Qamar Uddin Ahmed², Sahena Ferdosh^{3

4}, Abul Bashar Mohammed Helaluddin², Md Shihabul Awal⁵, Murni Nazira Sarian⁶, Md Zaidul Islam Sarker^{1

7}, Zainul Amiruddin Zakaria⁸

Affiliations

¹ Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia (IIUM), Kuantan 25200, Pahang, Malaysia.
² Drug Discovery and Synthetic Chemistry Research Group, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, International Islamic University Malaysia (IIUM), Kuantan 25200, Pahang, Malaysia.
³ Western Pacific Tropical Research Center, College of Natural and Applied Sciences, University of Guam, Mangilao, GU 96923, USA.
⁴ Department of Plant Science, Faculty of Science, Kuantan Campus, International Islamic University Malaysia (IIUM), Kuantan 25200, Pahang, Malaysia.
⁵ Department of Food Science & Nutrition, Faculty of Engineering, Hajee Mohammad Danesh Science & Technology University, Dinajpur 5200, Bangladesh.
⁶ Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia.
⁷ Cooperative Research, Extension and Education Services (CREES), Northern Marianas College, Saipan, MP 96950, USA.
⁸ Borneo Research on Algesia, Inflammation and Neurodegeneration (BRAIN) Group, Department of Biomedical Sciences, Faculty of Medicines and Health Sciences, University Malaysia Sabah, Jalan UMS, Kota Kinabalu 88400, Sabah, Malaysia.

Abstract

The fruit of Phaleria macrocarpa have been traditionally used as an antidiabetic remedy in Malaysia and neighbouring countries. Despite its potential for diabetes treatment, no scientific study has ever been conducted to predict the inhibitor interaction of the protein α-glucosidase identified in an extract prepared with a non-conventional extraction technique. Hence, the major aim of this research was to evaluate the in vitro antioxidant, the α-glucosidase inhibitors, and the molecular dynamic simulations of the α-glucosidase inhibitors identified by Quadrupole Time-of-Flight Liquid Chromatography Mass Spectrometry (Q-ToF-LCMS) analysis. Initially, dry fruit were processed using non-conventional and conventional extraction methods to obtain subcritical carbon dioxide extracts (SCE-1 and SCE-2) and heating under reflux extract (HRE), respectively. Subsequently, all extracts were evaluated for their in vitro antioxidative and α-glucosidase inhibitory potentials. Subsequently, the most bioactive extract (SCE-2) was subjected to Q-ToF-LCMS analysis to confirm the presence of α-glucosidase inhibitors, which were then analysed through molecular dynamic simulations and network pharmacology approaches to confirm their possible mechanism of action. The highest inhibitory effects of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and α-glucosidase on SCE-2 was found as 75.36 ± 0.82% and 81.79 ± 0.82%, respectively, compared to the SCE-1 and HRE samples. The Q-ToF-LCMS analysis tentatively identified 14 potent α-glucosidase inhibitors. Finally, five identified compounds, viz., lupenone, swertianolin, m-coumaric acid, pantothenic acid, and 8-C-glucopyranosyleriodictylol displayed significant stability, compactness, stronger protein-ligand interaction up to 100 ns further confirming their potential as α-glucosidase inhibitors. Consequently, it was concluded that the SCE-2 possesses a strong α-glucosidase inhibitory effect due to the presence of these compounds. The findings of this study might prove useful to develop these compounds as alternative safe α-glucosidase inhibitors to manage diabetes more effectively.

Keywords: Phaleria macrocarpa fruit; bioactive compounds; molecular dynamic simulations; network pharmacology; subcritical CO2 extract; α-glucosidase.

Grants and funding

SRCG20-002-0002/UMP-IIUM-UiTM Sustainable Research Collaboration Grant 2020 from the University Malaysia Pahang (UPM) and Research Management Center, IIUM, Malaysia.