整合药效团及共价对接用于虚拟筛选JAK3抑制剂

大量研究表明JAK3与炎症疾病的发生、发展具有密切的关系,使得JAK3成为一个极具潜力的药物靶点。其中,JAK3共价抑制剂因其选择性高、活性强的特点受到广泛关注。但是,JAK3与其家族的其他成员同源性高,使得开发JAK3选择性抑制剂充满挑战。计算机虚拟筛选方法可以在分子水平对JAK3的结构特征进行针对性筛选,但是传统的共价对接方法效率较低、准确度欠佳,因此本文提出了一种结合药效团和共价对接的虚拟筛选策略。该联用方法从DrugBank数据库成功地筛选出已报道的JAK3临床抑制剂,表明了这种虚拟筛选不仅具有较高的效率,同时具备了较强的筛选准确性,为JAK3共价抑制剂的虚拟筛选提供一定的指导作用。

Virtual Screening of JAK3 Inhibitors integrating Pharmacophore and Covalent Docking

A large number of studies have shown that JAK3 is closely related to the occurrence and development of inflammatory diseases, making JAK3 a highly potential drug target. JAK3 covalent inhibitors have received extensive attention because of their high isoform-selectivity and strong bio-activity. However, JAK3 has high homology with other members of JAK family, making the development of JAK3 selective inhibitors full of challenges. Computer simulation could focus on the structural characteristics of JAK3 at the molecular level and perform the virtual screening against JAK3. However, the traditional covalent docking method has low efficiency and poor accuracy. Therefore, in the present study, a virtual screening strategy combining pharmacophores and covalent docking was developed. The combined method successfully screened the reported JAK3 clinical inhibitor from the DrugBank database, indicating that this integrating virtual screening not only has strong efficiency, but also has high screening accuracy. It may provide some guidance for the virtual screening of novel JAK3 covalent inhibitors.