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Kinetics and molecular docking studies of pimarane-type diterpenes as protein tyrosine phosphatase (PTP1B) inhibitors from Aralia continentalis roots
- Kinetics and molecular docking studies of pimarane-type diterpenes as protein tyrosine phosphatase (PTP1B) inhibitors from Aralia continentalis roots
- Jung H.A.; Cho Y.S.; Oh S.H.; Lee S.; Min B.-S.; Moon K.H.; Choi J.S.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Archives of Pharmacal Research
- vol. 36, no. 8, pp. 957 - 965
- SCIE; SCOPUS; KCI
- Since insulin sensitivity to cells is attributed to phosphorylation of the insulin receptor (IR), protein tyrosine phosphatase 1B (PTP1B), which dephosphorylates the tyrosine residues of IR proteins, is primarily responsible for insulin resistance in type 2 diabetes. Therefore, PTP1B inhibitors ameliorating the insulin-dependent signaling pathway are potential therapeutic candidates for the treatment and prevention of diabetes. As part of our continuous search for diterpenes derived from Aralia continentalis as potent PTP1B inhibitors, five active diterpenoids, including ent-pimara-8(14),15-diene- 19-oic acid (1); 7-oxo-ent-pimara-8(14),15-diene-19-oic acid (2); 7β-hydroxy-ent-pimara-8(14),15-diene-19-oic acid (3); ent-pimara-8(14),15- diene-19-ol (4); 8α-hydroxy-ent-pimara-15-en-19-ol (5); and ent-kaur-16-en-19-oic-acid (6) were investigated using the enzyme kinetic assay. With the exception of 1 showing mixed inhibition, compounds 2 and 4-6 exhibited noncompetitive inhibition against PTP1B with K i values ranging 3.29-12.86 μM. In particular, 2 with an oxo group in the C-7 position showed increased PTP1B inhibition compared to nonsubstituted 1. Based on the structure and activity relationship, the 3D docking simulations of 1, 2, and 3 were also performed. Compounds 1-3 showed negative binding energies of -5.3 to -6.1 kcal/mol and a high affinity to PTP1B residues (Phe182 and Asp181 in the WPD loop; Cys215 in the active sites; Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221, Gln262, and Gln266 in the pocket site), indicating that they may stabilize the open form and generate tighter binding to the catalytic sites of PTP1B. The enzymatic kinetics and docking results clearly indicate the promising potential of pimarane-type diterpenes as PTP1B inhibitors. © 2013 The Pharmaceutical Society of Korea.
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