Protein Flexibility in Docking-Based Virtual Screening: Discovery of Novel Lymphoid-Specific Tyrosine Phosphatase Inhibitors Using Multiple Crystal Structures
Protein Flexibility in Docking-Based Virtual Screening: Discovery of Novel Lymphoid-Specific Tyrosine Phosphatase Inhibitors Using Multiple Crystal Structures
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基于对接的虚拟筛选中的蛋白质灵活性：利用多种晶体结构发现新型淋巴特异性酪氨酸磷酸酶抑制剂
DOI：
10.1021/acs.jcim.5b00344
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发表时间：
2015-09-01
影响因子：
5.6
通讯作者：
Fang, Hao
中科院分区：
文献类型：
--
作者：
Hou, Xuben;Li, Kangshuai;Fang, Hao
结合蛋白质灵活性是基于对接的虚拟筛选的主要挑战。随着可用晶体结构数量的不断增加，与多个蛋白质结构的整体对接是处理蛋白质灵活性的有效方法。在此，我们报告了使用多个晶体结构的基于对接的虚拟屏幕的成功应用，以发现淋巴特异性酪氨酸磷酸酶（LYP）的新型抑制剂，LYP是自身免疫性疾病的潜在药物靶点。适当使用多种蛋白质结构可以比单一结构更好地富集已知抑制剂的回收。随后，选择了最佳的 LYP 结构集合，并将其用于基于对接的虚拟筛选。在 23 种命中化合物中鉴定出 8 种新型 LYP 抑制剂（IC50 范围为 7.95 至 56.6 μM）。进一步的研究表明，最活跃的化合物 B15 比其他蛋白磷酸酶具有一定的选择性，并且可以有效上调 Jurkat T 细胞中 TCR（T 细胞受体）介导的信号传导。这些新的成果不仅为开发用于自身免疫性疾病的治疗剂提供了良好的起点，而且还证明了在基于对接的虚拟筛选中选择适当的蛋白质结构集合比使用单一蛋白质构象具有优势。
Incorporating protein flexibility is a major challenge for docking-based virtual screening. With an increasing number of available crystal structures, ensemble docking with multiple protein structures is an efficient approach to deal with protein flexibility. Herein, we report the successful application of a docking-based virtual screen using multiple crystal structures to discover novel inhibitors of lymphoid-specific tyrosine phosphatase (LYP), a potential drug target for autoimmune diseases. The appropriate use of multiple protein structures allowed a better enrichment than a single structure in the recovery of known inhibitors. Subsequently, an optimal ensemble of LYP structures was selected and used in docking-based virtual screening. Eight novel LYP inhibitors (IC50 ranging from 7.95 to 56.6 μM) were identified among 23 hit compounds. Further studies demonstrated that the most active compound B15 possessed some selectivity over other protein phosphatases and could effectively up-regulate TCR (T cell receptor)-mediated signaling in Jurkat T cells. These novel hits not only provided good starting points for the development of therapeutic agents useful in autoimmune diseases but also demonstrated the advantages of choosing an appropriate ensemble of protein structures in docking-based virtual screening over using a single protein conformation.