酪氨酸蛋白激酶BLK，亦称B细胞淋巴细胞激酶（BLK），是主要在B细胞中表达的非受体酪氨酸激酶。BLK在B细胞信号传导中起关键作用，尤其对B细胞的发育和成熟至关重要。增加的BLK表达与多种复杂疾病有关，包括自身免疫性疾病以及B细胞特定的恶性肿瘤，如淋巴瘤和白血病。由于BLK在B细胞信号传导中的重要参与，它已成为药物开发的有希望的靶标，为研发用于对抗这些疾病的新型治疗提供了潜力。BLK的小分子抑制剂具有潜在的治疗干预作用，但是寻找有效且选择性的抑制剂仍具有挑战性。在这种背景下，天然化合物作为发现BLK新型抑制剂的宝贵资源具有显著潜力。在本研究中，采用基于结构的虚拟筛选IMPPAT 2文库，识别具有潜力的候选物作为BLK抑制剂。该研究的对照分子为已知的BLK抑制剂Dasatinib。经过多步骤的筛选，两种分子（Withanolide I和Mexogenin）基于其较高的结合亲和力、连体效率和特异性相互作用显示出对BLK具有潜力。这些化合物与BLK的活性位点残基发生了多个显著的相互作用。分子动力学（MD）模拟研究表明，两种候选分子都与BLK的结合口袋保持结合。综上所述，这些发现为指导未来的研究探索和开发针对不同复杂疾病（如自身免疫性疾病，淋巴瘤和白血病）的治疗提供了宝贵的见解。Ramaswamy H. Sarma通讯录用。

Tyrosine-protein kinase BLK, also known as B-cell lymphocyte kinase (BLK), is a non-receptor tyrosine kinase that is primarily expressed in B-cells. BLK plays a key role in B-cell signaling, particularly in B-cell development and maturation. The increased expression of BLK has been linked to various complex diseases, including autoimmune disorders, and specific malignancies of B cells, such as lymphomas and leukemias. Due to its significant involvement in B-cell signaling, BLK has emerged as a promising target for drug development, offering the potential for developing novel therapeutics to combat these diseases. Small molecule inhibitors of BLK hold great potential for therapeutic intervention; however, discovering potent and selective inhibitors remains challenging. Within this context, natural compounds hold significant potential as a valuable resource for discovering novel inhibitors of BLK. In the current study, a structure-based virtual screening of the IMPPAT 2 library was employed to identify promising candidates with potential as inhibitors of BLK. The control molecule for this study was the known BLK inhibitor, Dasatinib. After a multi-step filtering process, two molecules (Withanolide I and Mexogenin) demonstrated potential against BLK based on their superior binding affinity, ligand efficiency, and specific interaction. Interaction analysis of these compounds revealed several significant interactions with the active site residues of BLK. Both proposed molecules remained bound to the binding pocket of BLK, as indicated by the molecular dynamics (MD) simulation study. Taken together, these findings provide valuable insights for guiding future research endeavors and translational efforts in developing therapeutics for different complex diseases, such as autoimmune disorders, lymphomas, and leukemias.Communicated by Ramaswamy H. Sarma.