Janus 激酶 3 (JAK3) 是酪氨酸激酶 JAK 家族的成员，其抑制仍然是开发自身免疫性疾病（尤其是癌症和类风湿性关节炎）治疗方法的重要研究领域。最近发现的一种新的 JAK3 蛋白 PDB ID：4Z16 为开发能够与 Cys909 残基形成共价键的抑制剂提供了令人兴奋的可能性，从而有助于抑制 JAK3。使用蒙特卡罗方法并采用各种内部和外部技术构建和验证了强大的预测模型。这种方法预测了 11 种新分子，随后对其进行过滤，以鉴定出 6 种表现出有效 pIC50 值的化合物。然后对这些候选药物进行 ADMET 分析、分子对接（包括与 FDA 批准的药物托法替尼的可逆-可逆对接，以及新设计化合物的可逆-不可逆对接）、300ns 的分子动力学 (MD) 分析和计算的自由结合能。结果表明这些化合物有望作为 JAK3 抑制剂。总之，与各种建模方法中的其他化合物相比，新化合物表现出了良好的结果。这些研究的集体发现为共价 JAK3 抑制剂的潜在治疗应用提供了宝贵的见解，为开发自身免疫性疾病的新疗法提供了有希望的方向。由 Ramaswamy H. Sarma 传达。

Inhibition of Janus kinase 3 (JAK3), a member of the JAK family of tyrosine kinases, remains an essential area of research for developing treatments for autoimmune diseases, particularly cancer and rheumatoid arthritis. The recent discovery of a new JAK3 protein, PDB ID: 4Z16, offers exciting possibilities for developing inhibitors capable of forming a covalent bond with the Cys909 residue, thereby contributing to JAK3 inhibition. A powerful prediction model was constructed and validated using Monte Carlo methods, employing various internal and external techniques. This approach resulted in the prediction of eleven new molecules, which were subsequently filtered to identify six compounds exhibiting potent pIC50 values. These candidates were then subjected to ADMET analysis, molecular docking (including reversible-reversible docking with tofacitinib, an FDA-approved drug, and reversible-irreversible docking for the newly designed compounds), molecular dynamics (MD) analysis for 300 ns, and calculation of free binding energy. The results suggested that these compounds hold promise as JAK3 inhibitors. In summary, the new compounds have exhibited favorable outcomes compared to other compounds across various modeling approaches. The collective findings from these investigations provide valuable insights into the potential therapeutic applications of covalent JAK3 inhibitors, offering a promising direction for the development of novel treatments for autoimmune disorders.Communicated by Ramaswamy H. Sarma.