Centre for Biotechnology, Anna University, Chennai, India.
J Chem Inf Model. 2012 Aug 27;52(8):2004-12. doi: 10.1021/ci200581g. Epub 2012 Jul 19.
Protein tyrosine phosphatase 1B (PTP1B), a major negative regulator of the insulin and leptin signaling pathway, is a potential target for therapeutic intervention against diabetes and obesity. The recent discovery of an allosteric site in PTP1B has created an alternate strategy in the development of PTP1B targeted therapy. The current study investigates the molecular interactions between the allosteric site of PTP1B with two caffeoyl derivatives, chlorogenic acid (CGA) and cichoric acid (CHA), using computational strategies. Molecular docking analysis with CGA and CHA at the allosteric site of PTP1B were performed and the resulting protein-ligand complexes used for molecular dynamics simulation studies for a time scale of 10 ns. Results show stable binding of CGA and CHA at the allosteric site of PTP1B. The flexibility of the WPD loop was observed to be constrained by CGA and CHA in the open (inactive), providing molecular mechanism of allosteric inhibition. The allosteric inhibition of CGA and CHA of PTP1B was shown to be favorable due to no restriction by the α-7 helix in the binding of CGA and CHA at the allosteric binding site. In conclusion, our results exhibit an inhibitory pattern of CGA and CHA against PTP1B through potent binding at the allosteric site.
蛋白酪氨酸磷酸酶 1B（PTP1B）是胰岛素和瘦素信号通路的主要负调节剂，是治疗糖尿病和肥胖症的潜在靶点。最近在 PTP1B 中发现了一个变构位点，为开发针对 PTP1B 的靶向治疗提供了另一种策略。本研究采用计算策略研究了 PTP1B 变构位点与两种咖啡酰衍生物——绿原酸（CGA）和菊苣酸（CHA）之间的分子相互作用。在 PTP1B 的变构位点进行了 CGA 和 CHA 的分子对接分析，并将得到的蛋白-配体复合物用于 10 ns 时间尺度的分子动力学模拟研究。结果表明，CGA 和 CHA 稳定结合在 PTP1B 的变构位点。观察到 WPD 环的灵活性由于 CGA 和 CHA 的存在而在开放（非活性）状态下受到限制，为变构抑制提供了分子机制。由于 CGA 和 CHA 在变构结合位点的结合不受 α-7 螺旋的限制，因此 CGA 和 CHA 对 PTP1B 的变构抑制是有利的。总之，我们的结果表明 CGA 和 CHA 通过在变构位点的有效结合对 PTP1B 表现出抑制模式。
