Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance

Sökning: WFRF:(Feng Bo) > Discovery and biolo...

Feng, BoYangzhou Univ, Affiliated Hosp, Dept Pharm, Yangzhou 225000, Peoples R China. (författare)

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 mu M for PTP1B, and 2.5 and 5.2 mu M 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.

Zhang, JieChinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Beijing, Peoples R China. (författare)
Liu, ZhenYangzhou Univ, Affiliated Hosp, Dept Neurol, Yangzhou, Peoples R China. (författare)
Xu, YuanYangzhou Univ, Affiliated Hosp, Dept Pharm, Yangzhou 225000, Peoples R China. (författare)
Hu, HuabinUppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab,Inst Canc Res, Ctr Canc Drug Discovery, Div Canc Therapeut, London, England.(Swepub:uu)huahu560 (författare)
Yangzhou Univ, Affiliated Hosp, Dept Pharm, Yangzhou 225000, Peoples R China.Chinese Acad Med Sci & Peking Union Med Coll, Inst Mat Med, Beijing, Peoples R China. (creator_code:org_t)

Av författaren/redakt...: Feng, Bo; Zhang, Jie; Liu, Zhen; Xu, Yuan; Hu, Huabin

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Läkemedelskemi

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