Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator that plays an important role in many signaling pathways, especially those associated with insulin resistance. In this study, we investigated the anti-diabetic potential of 12 natural tanshinones isolated from Salvia miltiorrhiza (S. miltiorrhiza) Bunge (Lamiaceae), deoxyneocryptotanshinone (1), grandifolia F (2), ferruginol (3), cryptotanshinone (4), tanshinone IIA (5), tanshinol B (6), tanshinone IIB (7), tanshinonal (8), methyl tanshinonate (9), 15,16-dihydrotanshinone I (10), tanshinone I (11), and dehydrodanshenol A (12) and evaluated their inhibitory activity against PTP1B. Tanshinones 4, 6 and 12 exhibited potent PTP1B inhibitory activity with IC50 values of 5.5 ± 0.9, 4.7 ± 0.4 and 8.5 ± 0.5 μM, respectively. In addition, tanshinones 1-3, 5 and 7-11 showed promising dose-dependent inhibition of PTP1B over IC50 values ranging from 18.6 to 254.8 μM. Enzyme kinetic analysis of PTP1B inhibition revealed that 4 and 6 were mixed -noncompetitive type inhibitors, whereas 12 was a classical-noncompetitive type inhibitor. Furthermore, 4, 6 and 12 were docked with the PTP1B enzyme using molecular docking simulations (AutoDock 4.2) and exhibited negative binding energy (-6.4 to -8.7 kcal/mol), indicating high binding affinity to PTP1B active site residues. Structure-activity relationships (SAR) analysis revealed that structural modifications of ring A and furan or dihydrofuran ring D on the basic structure of tanshinones influenced their activity. Overall, results indicated that tanshinones from S. miltiorrhiza are potential anti-diabetic candidates that should be explored in the development of preventive and therapeutic modalities for the treatment of diabetes as well as diabetes-associated complications.

中文翻译：

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丹参根中天然丹参酮对蛋白酪氨酸磷酸酶1B的抑制活性。

蛋白质酪氨酸磷酸酶1B（PTP1B）是一种负调节剂，在许多信号通路中，尤其是与胰岛素抵抗相关的信号通路中起着重要作用。在这项研究中，我们研究了从丹参（S. miltiorrhiza）Bunge（Lamiaceae），脱氧新隐丹参酮（1），大叶F（2），铁氧还蛋白（3），隐丹参酮（4），丹参酮IIA（5），丹参酚B（6），丹参酮IIB（7），丹参酮（8），丹参酮酸甲酯（9），15,16-二氢丹参酮I（10），丹参酮I（11）和脱氢丹酚A（12 ），并评估其对PTP1B的抑制活性。丹参酮4、6和12表现出强大的PTP1B抑制活性，IC50值分别为5.5±0.9、4.7±0.4和8.5±0.5μM。另外，tanshinones 1-3，图5和7-11显示了对PTP1B的剂量依赖性抑制，其IC50值范围为18.6至254.8μM。对PTP1B抑制的酶动力学分析表明，有4种和6种是混合的非竞争性抑制剂，而12种是经典的非竞争性抑制剂。此外，使用分子对接模拟（AutoDock 4.2）将4、6和12与PTP1B酶对接，并表现出负结合能（-6.4至-8.7 kcal / mol），表明对PTP1B活性位点残基的结合亲和力高。结构-活性关系（SAR）分析表明，丹参酮基本结构上环A和呋喃或二氢呋喃环D的结构修饰会影响其活性。总的来说，结果表明丹参酮来自S。