Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance
Copyright © 2023 Elsevier Ltd. All rights reserved..
In this study, a virtual screening pipeline comprising ligand-based and structure-based approaches was established and applied for the identification of dual PTP1B and ACP1 inhibitors. As a result, a series of benzoic acid derivatives was discovered, and compound H3 and S6 demonstrated PTP1B and ACP1 inhibitory activity, with IC50 values of 3.5 and 8.2 μM for PTP1B, and 2.5 and 5.2 μM for ACP1, respectively. Molecular dynamics simulations illustrated that H3 interacted with critical residues in the active site, such as Cys215 and Arg221 for PTP1B, and Cys17 and Arg18 for ACP1. Enzymatic kinetic research indicated that identified inhibitors competitively inhibited PTP1B and ACP1. Additionally, cellular assays demonstrated that H3 and S6 effectively increased glucose uptake in insulin-resistant HepG2 cells while displaying very limited cytotoxicity at their effective concentrations. In summary, H3 and S6 represent novel dual-target inhibitors for PTP1B and ACP1, warranting further investigation as potential agents for the treatment of diabetes.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:97 |
|---|---|
| Enthalten in: |
Bioorganic & medicinal chemistry - 97(2024) vom: 01. Jan., Seite 117545 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Feng, Bo [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.01.2024 Date Revised 05.01.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.bmc.2023.117545 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM365611662 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM365611662 | ||
| 003 | DE-627 | ||
| 005 | 20240108142603.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bmc.2023.117545 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1250.xml |
| 035 | |a (DE-627)NLM365611662 | ||
| 035 | |a (NLM)38070352 | ||
| 035 | |a (PII)S0968-0896(23)00393-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Feng, Bo |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.01.2024 | ||
| 500 | |a Date Revised 05.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a In this study, a virtual screening pipeline comprising ligand-based and structure-based approaches was established and applied for the identification of dual PTP1B and ACP1 inhibitors. As a result, a series of benzoic acid derivatives was discovered, and compound H3 and S6 demonstrated PTP1B and ACP1 inhibitory activity, with IC50 values of 3.5 and 8.2 μM for PTP1B, and 2.5 and 5.2 μM for ACP1, respectively. Molecular dynamics simulations illustrated that H3 interacted with critical residues in the active site, such as Cys215 and Arg221 for PTP1B, and Cys17 and Arg18 for ACP1. Enzymatic kinetic research indicated that identified inhibitors competitively inhibited PTP1B and ACP1. Additionally, cellular assays demonstrated that H3 and S6 effectively increased glucose uptake in insulin-resistant HepG2 cells while displaying very limited cytotoxicity at their effective concentrations. In summary, H3 and S6 represent novel dual-target inhibitors for PTP1B and ACP1, warranting further investigation as potential agents for the treatment of diabetes | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Antidiabetic agents | |
| 650 | 4 | |a Dual PTP1B-ACP1 inhibitors | |
| 650 | 4 | |a Pharmacophore | |
| 650 | 4 | |a Virtual screening | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Insulin |2 NLM | |
| 650 | 7 | |a Protein Tyrosine Phosphatase, Non-Receptor Type 1 |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a PTPN1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a ACP1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 650 | 7 | |a Protein Tyrosine Phosphatases |2 NLM | |
| 650 | 7 | |a EC 3.1.3.48 |2 NLM | |
| 700 | 1 | |a Zhang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhen |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Hu, Huabin |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Bioorganic & medicinal chemistry |d 1994 |g 97(2024) vom: 01. Jan., Seite 117545 |w (DE-627)NLM074978543 |x 1464-3391 |7 nnns |
| 773 | 1 | 8 | |g volume:97 |g year:2024 |g day:01 |g month:01 |g pages:117545 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.bmc.2023.117545 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 97 |j 2024 |b 01 |c 01 |h 117545 | ||