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Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies

Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previo...

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Autores principales: Ha, Manh Tuan, Shrestha, Srijan, Tran, Thu Huong, Kim, Jeong Ah, Woo, Mi Hee, Choi, Jae Sue, Min, Byung Sun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Pharmaceutical Society of Korea 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518952/
https://www.ncbi.nlm.nih.gov/pubmed/32978714
http://dx.doi.org/10.1007/s12272-020-01269-4
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author Ha, Manh Tuan
Shrestha, Srijan
Tran, Thu Huong
Kim, Jeong Ah
Woo, Mi Hee
Choi, Jae Sue
Min, Byung Sun
author_facet Ha, Manh Tuan
Shrestha, Srijan
Tran, Thu Huong
Kim, Jeong Ah
Woo, Mi Hee
Choi, Jae Sue
Min, Byung Sun
author_sort Ha, Manh Tuan
collection PubMed
description Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC(50) values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC(50) = 15.10 µM) and ursolic acid (IC(50) = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC(50) values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1–11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications.
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spelling pubmed-75189522020-09-28 Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies Ha, Manh Tuan Shrestha, Srijan Tran, Thu Huong Kim, Jeong Ah Woo, Mi Hee Choi, Jae Sue Min, Byung Sun Arch Pharm Res Research Article Among the 2-arylbenzofuran derivatives isolated from Morus alba, the farnesylated 2-arylbenzofuran is a rarer constituent. The derivative has been reported to exert anti-obesity effect; however, its inhibitory effect on protein tyrosine phosphatase 1B (PTP1B) has not been investigated. In the previous study, the presence of the farnesyl group in the structure of 2-arylbenzofurans was found to have positive influences on their pancreatic lipase inhibitory activity. In the present study, we have confirmed the authenticity of the notation based on the PTP1B inhibitory activity of farnesylated 2-arylbenzofurans. Specifically, two farnesylated 2-arylbenzofurans [morusalfurans B (2) and C (3)] showed strong inhibitory effects on PTP1B with IC(50) values of 8.92 and 7.26 µM, respectively, which was significantly higher than that of the positive controls [sodium orthovanadate (IC(50) = 15.10 µM) and ursolic acid (IC(50) = 11.34 µM)]. Besides, two 2-arylbenzofurans [morusalfurans A (1) and F (6)], one flavonoid [morusalnol B (9)], and one geranylated stilbene [morusibene A (11)] exhibited PTP1B inhibition with IC(50) values ranging from 11.02 to 26.56 µM. Kinetic studies revealed compounds 2, 3, 6, and 11 as mixed type PTP1B inhibitors, while 1 and 9 are known as noncompetitive. Molecular docking simulations demonstrated that these active compounds can bind with the respective catalytic or/and allosteric sites of PTP1B with negative binding energies and the results are in accordance with that of the kinetic studies. To the best of our knowledge, this is the first time, the PTP1B inhibitory activity of eleven compounds (1–11), as well as the mechanism of action underlying the effects on PTP1B enzyme of the active compounds, were investigated. In vitro and in silico results suggest that the farnesylated 2-arylbenzofurans from M. alba may potentially be utilized as an effective treatment therapy for type 2 diabetes mellitus and its associated complications. Pharmaceutical Society of Korea 2020-09-25 2020 /pmc/articles/PMC7518952/ /pubmed/32978714 http://dx.doi.org/10.1007/s12272-020-01269-4 Text en © The Pharmaceutical Society of Korea 2020 This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.
spellingShingle Research Article
Ha, Manh Tuan
Shrestha, Srijan
Tran, Thu Huong
Kim, Jeong Ah
Woo, Mi Hee
Choi, Jae Sue
Min, Byung Sun
Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title_full Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title_fullStr Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title_full_unstemmed Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title_short Inhibition of PTP1B by farnesylated 2-arylbenzofurans isolated from Morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
title_sort inhibition of ptp1b by farnesylated 2-arylbenzofurans isolated from morus alba root bark: unraveling the mechanism of inhibition based on in vitro and in silico studies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518952/
https://www.ncbi.nlm.nih.gov/pubmed/32978714
http://dx.doi.org/10.1007/s12272-020-01269-4
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