Appraisal of the anti-diabetic potential of polyphenolic compounds from Viscum combreticola Engl.: In vitro a-glucosidase inhibition, LC-ESI-QTOF- MS coupled to pre-column DPPH antioxidative assay, network pharmacology and molecular docking analysis

Viscum combreticola Engl. is currently used in African medicine for treating various ailments including diabetes. However, modernizing plant-based traditional medicine is a considerable challenge due to lack of scientific information linked to its therapeutic efficacy given the complexity of plant extracts. Herein, methanolic extracts were evaluated for their anti-diabetic and antioxidative properties through the a-glucosidase in vitro inhibition assay and LC-ESI-Q-TOF-MS coupled to pre-column DPPH assay, respectively. Furthermore, metabolic profiling of V. combreticola extracts was conducted using UHPLC-q-TOF-MS technique. The identified chemically diverse polyphenols comprising of 19 diacylated chlorogenic acids (CGAs) and 12 flavonoids were explored for their mode of action in managing type 2 diabetes mellitus (T2DM) using network pharmacology. Systematic pharmacological analysis revealed that CGAs and flavonoids characterized by structural similarities or analogous spatial arrangements exhibited interactions with identical target proteins. Isomers of CGAs diacylated at carbon positions 3,4 (3,4-diCQA; 3-p-Co-4-CQA and 3-C-4-p-CoQA) as well as 4,5 (4,5diCQA;4-C-5-p-CoQA; and 4-p-Co-5-CQA) of quinic acid were found to be hub therapeutic agents against T2DM related target proteins. The investigated CGAs and flavonoids could be playing a major role in the management of T2DM and its complications by synergistically regulating key protein targets. These include matrix metalloproteinase 2 (MMP2), caspase 3 (CASP3), protein kinase C alpha and delta (PRKCA and PRKCD), which are related to T2DM hub pathways such as the lipid and atherosceloresis, AGE-RAGE signalling pathway for diabetes complications and diabetic cardiomyopathy signalling pathways. Finally, molecular docking studies revealed that viscutin 2 and 3,4-diCQA were key potential inhibitors of a-glucosidase and MMP2, respectively. Therefore, the findings of this study suggest that isomerism in compounds might have pharmacological implications. Lastly, the anti-T2DM therapeutic effects of the polyphenols investigated in this study can serve as potential anti-diabetic agents for future experimental validation, particularly paying attention to isomerism.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of SAAB. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)