On the Inhibitability of Natural Products Isolated from Tetradium ruticarpum towards Tyrosine Phosphatase 1B (PTP1B) and α-Glucosidase (3W37): An In Vitro and In Silico Study

Abstract

Folk experiences suggest natural products in Tetradium ruticarpum can be effective inhibitors towards diabetes-related enzymes. The compounds were experimentally isolated, structurally elucidated, and tested in vitro for their inhibition effects on tyrosine phosphatase 1B (PTP1B) and α-glucosidase (3W37). Density functional theory and molecular docking techniques were utilized as computational methods to predict the stability of the ligands and simulate interaction between the studied inhibitory agents and the targeted proteins. Structural elucidation identifies two natural products: 2-heptyl-1-methylquinolin-4-one (1) and 3-[4-(4-methylhydroxy-2-butenyloxy)-phenyl]-2-propenol (2). In vitro study shows that the compounds (1 and 2) possess high potentiality for the inhibition of PTP1B (IC50 values of 24.3 ± 0.8, and 47.7 ± 1.1 μM) and α-glucosidase (IC50 values of 92.1 ± 0.8, and 167.4 ± 0.4 μM). DS values and the number of interactions obtained from docking simulation highly correlate with the experimental results yielded. Furthermore, in-depth analyses of the structure–activity relationship suggest significant contributions of amino acids Arg254 and Arg676 to the conformational distortion of PTP1B and 3W37 structures overall, thus leading to the deterioration of their enzymatic activity observed in assay-based experiments. This study encourages further investigations either to develop appropriate alternatives for diabetes treatment or to verify the role of amino acids Arg254 and Arg676.

Curcumins from <em>Curcuma longa </em>Potential Inhibit PTP1B and α-Glucosidase: Experimental and Computational Study

“…This ranking were highly correlate with experimental data since the IC50 of tested compounds were: compound 1 (78.2 ± 0.2 μM), compound 2 (82.4 ± 0.8 μM), compound 3 (90.6 ± 1.0 μM), acarbose (147.2 ± 1.0 μM). As reported in previous study [22], Arg676 was assumed to display important role in the functional of α-glucosidase (3W37). Interaction formed with this residue seem to induce sevear conformational changes on the enzyme PTP1B, thus, causing loss of its normal functionality.…”

“…But, their inhibitory effects were moderate at 50 μg/mL and at mM level [34,35]. In our experimental assay, α-glucosidase enzyme was obtained from rat intestine and the positive control acarbose showed a stable IC50 value [22]. Consequently, the result obtained in this study was accurate and reachable.…”

“…Regarding to α-glucosidase inhibitory experimental assay, acarbose and curcumins (1-3) were tested using α-glucosidase enzyme from rat intestinal tract. In this assay, acarbose displayed a similar inhibitory IC50 value (147.2 ± 1.0 μM) toward α-glucosidase [22]. Furthermore, curcumin (1) potentially inhibited the action of α-glucosidase with an IC50 value of 78.2 ± 0.2 μM, almost two times stronger than acarbose.…”

“…PTP1B enzyme was obtained from Biomol International LP, Plymouth Meeting, Pennsylvania, PA, USA, and the experimental assay was performed similar with previous method [22].…”

Untargeted LC-MS/MS-Based Multi-Informative Molecular Networking for Targeting the Antiproliferative Ingredients in Tetradium ruticarpum Fruit

“…Furthermore, both evodiamine and rutaecarpine possessed hepatoprotection [ 21 ], vasodilatory [ 22 ], and anti-inflammatory [ 23 ] activities. The quinolone alkaloids of TR fruit such as evocarpine and schinifoline have been reported to exhibit antimicrobial activity [ 24 , 25 ], and schinifoline has also been shown to possess hypoglycemic potential by inhibiting diabetes-related enzymes [ 26 ]. Limonin is the major terpenoid of TR fruit with diverse pharmacological activities, such as antibacterial, antivirus, anticancer, and anti-inflammatory properties [ 27 ].…”