MOLECULAR ANNOTATION AND DOCKING OF SECONDARY METABOLITES OF MEDICINAL PLANTS FOR THE INHIBITION OF ENZYMES OF DIABETIC TARGET

Abstract

Type-2 diabetes mellitus (T2DM), a severe endocrine disorder indicated by an unusual elevation in blood glucose levels due to a deficiency in insulin secretion, action, or both, is expected to be the third most common risk factor for premature death. The alarming rise in diabetes prevalence, as well as the surging costs associated with managing diabetes and its complications, highlights the necessity for safer, more efficacious, and cost-effective alternative therapies. Over 1200 plant sources have been documented in ethnomedicine for the treatment of diabetes, providing an additional and valuable source for the discovery of novel antidiabetic compounds. Plants have potential therapeutic properties because of the presence of phytochemicals such as alkaloids, flavonoids, terpenes, phenols, coumarins, and others which reduce cellular stress and prevent cytotoxicity from various agents. Biologically active polyphenols and flavonoids can have antidiabetic properties which could increase insulin secretions or decrease intestinal sugar absorption by inhibiting α-amylase and α-glucosidase. Similarly, lipid metabolism could be controlled by inhibiting pancreatic lipase because lipids are also associated with Diabetes Mellitus. Increased amounts of fatty acids and glucose cause glucolipotoxicity, which decreases insulin production, impairs insulin gene expression, and causes β-cells to die through apoptosis. Moreover, microbial infections cause the body to experience stress, which can lead to hormonal abnormalities that influence insulin production and raise blood sugar levels. This study, therefore, focuses on the evaluation of the inhibitory activities of enzymes of diabetic targets and secondary metabolites profiling of Mimosa pudica, Bergenia ciliata, and Phyllanthus emblica chosen based on an ethnobotanical knowledge and literature review. Total flavonoid contents (TFC), total phenolic contents (TPC), and antioxidant activities of their extracts were also measured. Additionally, phytoconstituents responsible for inhibiting the enzymes of diabetic targets were identified through in-silico analyses. Higher TPC and TFC have been found in the EA extracts of all three medicinal plants under study. The high TFC value was also shown by the crude methanolic extract of B. ciliata. Effective antioxidant activities were demonstrated by P. emblica and M. pudica EA extracts (IC50: 11.98 ± 0.36 µg/mL and 21.39 ± 3.76 µg/mL, respectively), as well as B. ciliata aqueous extract (IC50: 16.99 ± 2.56 µg/mL). The IC50 values for the EA extract of B. ciliata against α-amylase and α-glucosidase were 38.50 ± 1.32 µg/mL and 3.41± 0.04 µg/mL respectively. The hexane fraction of M. pudica and P. emblica with IC50 of 0.49 ± 0.02 and 2.45 ± 0.003 mg/mL showed a higher pancreatic lipase inhibitory activity while methanolic extract of B. ciliata inhibited lipase more effectively (IC50: 1.07 ± 0.03 mg/mL). Higher antimicrobial activity was demonstrated by the EA extracts against Shigella sonnei ATCC 25931, Salmonella typhi ATCC 14028, Escherichia coli ATCC 25923, and Staphylococcus aureus ATCC 25923. The range of the MIC for the EA extracts of the medicinal plants included in this study was 1.56 to 6.25 mg/mL. Twenty-six significant secondary metabolites were identified through liquid chromatography-high resolution mass spectrometry (LC-HRMS) analysis of various extracts obtained through solvent/solvent partition from three selected plants. In silico analysis revealed that procyanidin B3 has the highest binding affinity toward enzymes of the diabetic target with the binding energy of -8.5, -9.1, and -9.5 kcal/mol for α-glucosidase, lipase, and α-amylase respectively. Furthermore, molecular annotated compounds interacted with these enzymes, supporting the efficacy and ethnobotanical uses of the selected plants for their inhibition and showing their therapeutic significance for treating diabetes.