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Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes.

ABSTRACT: Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = -45.02 kcal mol^-1 for alpha-amylase and -38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of -36.796 kcal mol^-1 for alpha-amylase and -29.622 kcal mol^-1 for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors' native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.

SUBMITTER: Ahmed S

PROVIDER: S-EPMC9316265 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveMedicinal plants and essentials oils are well known for diverse biological activities including antidiabetic potential. This study was designed to isolate essential oils from the leaves of Persicaria hydropiper L. (P. hydropiper), perform its phytochemical analysis, and explore its in vitro antidiabetic effects.Materials and methodsP. hydropiper leaves essential oils (Ph.Los) were extracted using a hydrodistillation apparatus and were subjected to phytochemical analysis using the gas chromatography mass spectrometry (GC-MS) technique. Ph.Lo was tested against two vital enzymes including α-glucosidase and α-amylase which are important targets in type-2 diabetes. The identified compounds were tested using in silico approaches for their binding affinities against the enzyme targets using MOE-Dock software.ResultsGC-MS analysis revealed the presence of 141 compounds among which dihydro-alpha-ionone, cis-geranylacetone, α-bulnesene, nerolidol, β-caryophyllene epoxide, and decahydronaphthalene were the most abundant compounds. Ph.Lo exhibited considerable inhibitory potential against α-glucosidase enzyme with 70% inhibition at 1000 μg mL-1 which was the highest tested concentration. The inhibitory activity of positive control acarbose was 77.30 ± 0.61% at the same tested concentration. Ph.Lo and acarbose exhibited IC50 of 170 and 18 µg mL-1 correspondingly. Furthermore, dose-dependent inhibitions were observed for Ph.Lo against α-amylase enzyme with an IC50 of 890 μg mL-1. The top-ranked docking conformation was observed for β-caryophyllene epoxide with a docking score of -8.3182 against α-glucosidase, and it has established seven hydrogen bonds and one H-pi interaction at the active site residues (Phe 177, Glu 276, Arg 312, Asp 349, Gln 350, Asp 408, and Arg 439). Majority of the identified compounds fit well in the binding pocket of Tyr 62, Asp 197, Glu 233, Asp 300, His 305, and Ala 307 active residues of α-amylase. β-Caryophyllene epoxide was found to be the most active inhibitor with a docking score of -8.3050 and formed five hydrogen bonds at the active site residues of α-amylase. Asp 197, Glu 233, and Asp 300 active residues were observed to be making polar interactions with the ligand.ConclusionsThe current study revealed that Ph.Lo is rich in bioactive metabolites which might contribute to its enzyme inhibitory potential. Inhibition of these enzymes is the key target in reducing postprandial hyperglycemia. However, further detailed in vivo studies are required for their biological and therapeutic activities.

Project description:Shortage in insulin secretion or degradation of produced insulin is the principal characteristic of the metabolic disorder of diabetes mellitus (DM). However, because the current medications for the treatment of DM have many detrimental side effects, it is necessary to develop more effective antidiabetic drugs with minimal side effects. Alpha-glucosidase and alpha-amylase inhibitors are directly implicated in the delay of carbohydrate digestion. Pharmacologically, these inhibitors could be targeted for the reduction in glucose absorption rate and, subsequently, decreasing the postprandial rise in plasma glucose and the risk for long-term diabetes complications. The main objectives of this research study were to isolate different phytochemical constituents present in the methanolic extract of Plectranthusecklonii and evaluate their alpha-glucosidase and alpha-amylase inhibitory activities and antioxidant capacity. The phytochemical investigation of the methanolic extract of P. ecklonii yielded three known compounds, viz. parvifloron D, F, and G (1-3, respectively). Parvifloron G was isolated for the first time from P. ecklonii. The in vitro bio-evaluation of the methanolic extract of P. ecklonii and its isolated compounds against alpha-glucosidase showed that 3 exhibited moderate inhibitory activity with IC50 values of 41.3 ± 1.2 μg/mL. Molecular docking analysis confirmed the alpha-glucosidase inhibitory activity demonstrated by 3. Additionally, strong antioxidant capacities were demonstrated by 3 and 1 on ORAC (28726.1 ± 8.1; 3942.9.6.6 ± 0.1 µM TE/g), respectively, which were comparable with the reference antioxidant epigallocatechingallate (EGCG). Furthermore, 3 also showed strong activity on TEAC (3526.1 ± 0.6 µM TE/g), followed by 2 (1069.3 ± 2.4 µM TE/g), as well as on FRAP (1455.4 ± 2.0 µM AAE/g). The methanolic extract of P. ecklonii is a rich source of abietane diterpenes with strong antioxidant activities. This is the first scientific report on alpha-glucosidase and alpha-amylase inhibitory activities, molecular docking, and antioxidant capacities of P. ecklonii constituents.

Project description:Diabetes mellitus (DM) is one of the most dangerous metabolic diseases with a high rate of mortality worldwide. It is well known that insulin resistance and deficiency in insulin production from pancreatic β-cells are the main characteristics of DM. Due to the detrimental side effects of the current treatment, there is a considerable need to develop new effective antidiabetic drugs, especially alpha-glucosidase and alpha-amylase inhibitors with lesser adverse effects. These inhibitors are known to be directly involved in the delay of carbohydrate digestion, resulting in a reduction of glucose absorption rate and, consequently, reducing the postprandial rise of plasma glucose, which can reduce the risk of long-term diabetes complications. Furthermore, natural products are well-known sources for the discovery of new bioactive compounds that can serve as scaffolds for drug discovery, including that of new antidiabetic drugs. The phytochemical investigation of Salvia aurita collected from Hogobach Pass, Eastern Cape Province, South Africa (SA), yielded four known abietane diterpenes namely carnosol (1), rosmanol (2), 7-methoxyrosmanol (3), 12-methoxycarnosic acid (4), and one flavonoid named 4,7-dimethylapigenin (5). Structural characterization of these isolated compounds was conducted using 1 and 2D NMR, in comparison with reported spectroscopic data. These compounds are reported for the first time from S. aurita. The biological evaluation of the isolated compound against alpha-glucosidase exhibited strong inhibitory activities for 3 and 2 with the half maximal inhibitory concentration (IC50) values of 4.2 ± 0.7 and 16.4 ± 1.1 µg/mL respectively, while 4 and 1 demonstrated strong alpha-amylase inhibitory activity amongst the isolated compounds with IC50 values of 16.2 ± 0.3 and 19.8 ± 1.4 µg/mL. Molecular docking analysis confirms the strong inhibitory activity of 3 against alpha-glucosidase. Additionally, excellent antioxidant capacities were displayed by 2, 1, and 3, respectively, with oxygen radical absorbance capacity (ORAC) (25.79 ± 0.01; 23.96 ± 0.01; 23.94 ± 0.02) mM Trolox equivalent (TE)/g; 1 and 2 as ferric-ion reducing antioxidant power (FRAP) (3.92 ± 0.002; 1.52 ± 0.002) mM ascorbic acid equivalent (AAE)/g; 5 and 2 as Trolox equivalent absorbance capacity (TEAC) (3.19 ± 0.003; 2.06 ± 0.003) mM TE/g. The methanolic extract of S. aurita is a rich source of abietane diterpenes with excellent antioxidant and antidiabetic activities that can be useful to modulate oxidative stress and might possibly be excellent candidates for the management of diabetes. This is the first scientific report on the phytochemical isolation and biological evaluation of the alpha-glucosidase and alpha-amylase inhibitory activities of Salvia aurita.

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Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes.

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