Protein tyrosine phosphatase 1B (PTP1B) is a potential drug target for diabetes and obesity. However, the design of PTP1B inhibitors that combine potency and bioavailability is a great challenge, and new leads are needed to circumvent this problem. Virtual screening (VS) workflows can be used to find new PTP1B inhibitors with little chemical similarity to existing inhibitors. Unfortunately, previous VS workflows for the identification of PTP1B inhibitors have several limitations, such as a small number of experimentally tested compounds and the low bioactivity of those compounds. We developed a VS workflow capable of identifying 15 structurally diverse PTP1B inhibitors from 20 compounds, the bioactivity of which was tested in vitro. Moreover, we identified two PTP1B inhibitors with the highest bioactivity reported by any VS campaign (i.e., IC₅₀ values of 1.4 and 2.1 μm), which could be used as new lead compounds.

中文翻译：

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结合基于配体和受体的虚拟筛选方法，鉴定结构多样的蛋白酪氨酸磷酸酶1B抑制剂

蛋白酪氨酸磷酸酶1B（PTP1B）是糖尿病和肥胖症的潜在药物靶标。但是，结合功效和生物利用度的PTP1B抑制剂的设计是一个巨大的挑战，需要新的线索来解决这个问题。虚拟筛选（VS）工作流程可用于查找与现有抑制剂化学相似性极低的新PTP1B抑制剂。不幸的是，以前用于鉴定PTP1B抑制剂的VS工作流程有几个局限性，例如少量的经过实验测试的化合物以及这些化合物的低生物活性。我们开发了一种VS工作流程，该工作流程能够从20种化合物中鉴定15种结构多样的PTP1B抑制剂，并在体外对其生物活性进行了测试。此外，我们确定了两种VS运动报告的具有最高生物活性的PTP1B抑制剂（即IC_50个的1.4和2.1μ值米），它可以被用作新的先导化合物。