化学
结合
药理学
噻唑烷二酮
蛋白质酪氨酸磷酸酶
生物化学
合理设计
组合化学
酪氨酸
糖尿病
2型糖尿病
内分泌学
医学
纳米技术
数学分析
材料科学
数学
作者
Suresh Thareja,Sant Kumar Verma,Akhlesh Kumar Jain,Manoj Kumar,Tilak Raj Bhardwaj
标识
DOI:10.1016/j.molstruc.2022.134546
摘要
• Structure guided designing of Biphenyl TZD conjugates as PTP1B Inhibitors • In silico ADMET screening to identify orally active drug-like candidates • Docking study to access target binding affinity and allosteric binding features • Synthesis and characterization of designed PTP1B inhibitors • In vitro PTP1B inhibitory assay and in vivo anti-hyperglycaemic efficacy study To achieve the unmet discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors, we have rationally designed novel biphenyl thiazolidinedione conjugates ( 8a-n ). The designed molecules were found fit on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening criteria of drug-likeness. Ligand-target binding study revealed that N-methyl benzoic acid derivative ( 8j ) was best target fit and displayed extended plausible binding interactions with phospho-tyrosine (pTyr) loop of PTP1B, a unique bidentate binding mode for PTP1B selectivity over other PTPs. The designed analogues ( 8a-n ) were synthesized (Scheme 1) and accessed for their in vitro PTP1B inhibitory potency, in vivo anti-hyperglycemic efficacy as well as the effect of treatment on weight and pancreatic safety. Molecules 8a-n showed moderate to good PTP1B inhibitory activity (IC 50 = 5.897-48.150 µM) compared to Suramin (IC 50 = 11.104 µM) and exhibited time-dependent in vivo efficacy, ranging from inferior to better, as compared to Pioglitazone. Moreover, 8j was found best pre-clinical candidate exhibiting good in vitro potency (IC 50 = 5.897 µM), better in vivo efficacy with the advantage of control in weight and pancreatic safety, compared to glitazone therapy.
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