Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Abstract

Natural products have played an important role in treating and preventing human diseases.1) An analysis of the origin of the drugs that were launched in the last twenty-five years showed that both natural products and semi-synthetic compounds, derived from natural origin, comprised 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds.2) Therefore, natural products are considered important sources for new drugs or lead optimization.2,3) The structural diversity of natural products combined with the fact that they were elaborated within living systems render them more "drug-like" than totally synthetic molecules. 4-7)Papaverine (Fig. 1A) is a prominent member of isoquinoline alkaloids isolated from opium poppy (Papaver somniferum L.).8) It exhibits non-selective smooth muscle relaxant effects, which prompted its widespread clinical use in the treatment of vasospasmic diseases.9-11) Papaverine increases the unidirectional K ϩ influx into muscles causing vasodilatation and muscle relaxant effects. The K ϩ flux is associated with increases in glucose uptake which could be one of the causes of hypoglycemia associated with papaverine use. 12)In a recent publication, we revealed a potent inhibitory action for berberine (Fig. 1B), another prominent isoquinoline alkaloid, against the anti-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B).13) The chemical similarity between berberine and papaverine combined with the fact that they share common biosynthetic origin, 14,15) prompted us to evaluate any possible inhibitory action of papaverine against h-PTP 1B. Furthermore, several reports have indicated that opiates, including papaverine, possess significant hypoglycemic properties. 16,17) The hypoglycemic mechanism of opiates is still uncertain. Furthermore, the hypoglycemic effect of papaverine is not well characterized using in vivo animal models.h-PTP 1B, a cytosolic non-receptor protein tyrosine phosphatase, has been implicated in the progression of diabetes because it acts as negative regulator of insulin signal transduction. h-PTP 1B directly catalyzes the dephosphorylation of cellular substrates of the insulin receptor kinase resulting in a down-regulation of insulin action. [18][19][20][21] Mice lacking functional h-PTP 1B showed enhanced tyrosine kinase activity and increased sensitivity to insulin. 22) In another animalbased approach, treatment with anti-sense oligonucleotide specific for h-PTP 1B resulted in normalization of blood glucose and insulin levels in animal models of type 2 diabetes. 23)Accordingly, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels in diabetic animal models. [24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo. The structural similarity between papa...

Protein Tyrosine Phosphatase 1B Inhibitors: A Molecular Level Legitimate Approach for the Management of Diabetes Mellitus

“…(168)(169)(170) inhibited PTP 1B in the mixed-type manner, indicating that they may bind both at the active site and an additional binding site of the PTP 1B enzyme. 179 The genus Siegesbeckia has been used as a traditional medicine, ''Hi-Chum'' in Korea (common name: Siegesbeckia herb), to treat inflammatory diseases.…”

“…Papaverine also exhibited potent in vitro inhibitory effect against recombinant h-PTP 1B (IC 50 1.20 mM) and significantly decreased fasting blood glucose level in vivo. 170 The genus Erythrina of the family Leguminosae comprises over 110 species that are widely distributed in tropical and subtropical regions, and representative species have been used in indigenous medicine. 171,172 In a continuing effort to search for natural PTP 1B inhibitors, Na et al reported three new 2-arylbenzofurans isolated from the stem bark of Erythrina addisoniae, which were found to exhibit potent in vitro PTP 1B inhibitory activities.…”

Natural and semisynthetic protein tyrosine phosphatase 1B (PTP1B) inhibitors as anti-diabetic agents

“…76 Chen et al demonstrated that berberine has insulinmimicking effects on both adipocytes and myocytes, which may occur through the inhibition of PTP1B activity and signicantly lower the blood glucose of diet-induced-obese (DIO) mice and db/db mice, but they do not increase insulin release and synthesis in vivo. 78 Three norditerpenoid alkaloids, nigelladines AÀC, and one pyrroloquinoline alkaloid, nigellaquinomine, possessing new skeletons were isolated from the seeds of Nigella glandulifera Freyn. 77 Papaverine (101, Fig.…”

Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades

“…Inspired by the structural similarity with 283, papaverine 284 was inferred to exhibit inhibitory activity. It was shown that 284 readily docked within the binding pocket of PTP1B in a low-energy orientation via an optimal set of attractive interactions [189] . Compound 284 exhibited a potent in vitro inhibitory effect (IC 50 =1.20 μmol/L), and significantly decreased fasting blood glucose levels of Balb/c mice in vivo.…”