State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington DC 20059, USA.
Bioorg Chem. 2019 May;86:224-234. doi: 10.1016/j.bioorg.2019.01.059. Epub 2019 Jan 28.
Protein tyrosine phosphatase 1B (PTP1B) has recently been identified as a potential target of Norathyriol. Unfortunately, Norathyriol is not a potent PTP1B inhibitor, which somewhat hinders its further application. Based on the fact that no study on the relationship of chemical structure and PTP1B inhibitory activity of Norathyriol has been reported so far, we attempted to perform structural optimization so as to improve the potency for PTP1B. Via structure-based drug design (SBDD), a rational strategy based on the binding mode of Norathyriol to PTP1B, we designed 26 derivatives with substitutions at the four phenolic hydroxyl groups of Norathyriol. By chemical synthesis and in vitro bioassay, we identified seven PTP1B inhibitors that were more potent than Norathyriol, of which XWJ24 showed the highest potency (IC: 0.6 μM). We also found out that XWJ24 was a competitive inhibitor and showed the 4.5-fold selectivity over its close homolog, TC-PTP. Through molecular docking of XWJ24 against PTP1B, we highlighted the essential role of its hydrogen bond with Asp181 for PTP1B inhibition and identified a potential halogen bond with Asp48 that was not observed for Norathyriol. The current data indicate that our SBDD strategy is effective to discover potent PTP1B-targeted Norathyriol derivatives, and XWJ24 is a promising lead compound for further development.
蛋白酪氨酸磷酸酶 1B（PTP1B）最近被鉴定为正丁基菲醇的潜在靶标。遗憾的是，正丁基菲醇不是一种有效的 PTP1B 抑制剂，这在一定程度上阻碍了其进一步的应用。鉴于目前尚无关于正丁基菲醇的化学结构与 PTP1B 抑制活性关系的研究，我们试图进行结构优化以提高其对 PTP1B 的效力。通过基于结构的药物设计（SBDD），基于正丁基菲醇与 PTP1B 的结合模式的合理策略，我们设计了 26 种在正丁基菲醇的四个酚羟基上进行取代的衍生物。通过化学合成和体外生物测定，我们鉴定出了 7 种比正丁基菲醇更有效的 PTP1B 抑制剂，其中 XWJ24 的活性最高（IC：0.6μM）。我们还发现 XWJ24 是一种竞争性抑制剂，对其近亲 TC-PTP 的选择性是其 4.5 倍。通过 XWJ24 与 PTP1B 的分子对接，我们强调了其与 Asp181 的氢键对于 PTP1B 抑制的重要作用，并确定了与 Norathyriol 不同的潜在卤键与 Asp48 的相互作用。目前的数据表明，我们的 SBDD 策略有效地发现了具有强效的针对 PTP1B 的正丁基菲醇衍生物，XWJ24 是进一步开发的有前途的先导化合物。
