Identifying potent Janus kinase 3 inhibitors using structure-guided virtual screening for inflammatory and neoplastic disease therapy

Janus kinases (JAKs) are potential therapeutic targets for anti-inflammatory and anti-cancer agents due to their involvement in cytokine signaling and cell proliferation. One of the major issues in the development of JAK inhibitors is the problem of selectivity for certain isoforms; since the isoforms are highly homologous, selective targeting is difficult. Of the JAKs, Janus kinase 3 (JAK3) which is mainly found in immune cells, is the most suitable isoform to target selectively to enhance the efficacy of treatment. In this study, we used a structure-based virtual screening method to screen PubChem for high-affinity JAK3 inhibitors using known JAK3-inhibitor complex structures. Through stringent filtering criteria, including structural similarity, physicochemical properties, and molecular interactions, we identified two promising compounds, CID:68715657 and CID:68585456, which showed potential JAK3 inhibition activity. These compounds showed better binding affinity than the parent molecules, and the structural modifications also improved the interaction with JAK3, indicating better potency and selectivity. Molecular dynamics (MD) simulations and MM-PBSA confirmed the stability of JAK3 complexes with CID:68715657 and CID:68585456, which further support their prospect as therapeutic targets of JAK3-related diseases. However, this study is limited by its reliance on computational predictions without experimental validation and the constraints of the PubChem database in capturing novel chemical scaffolds. Taken together, the results offer a sound basis for the further optimization of these compounds as highly effective and selective JAK3 inhibitors.

贾努斯激酶（Janus kinases, JAKs）可通过参与细胞因子信号转导与细胞增殖过程，成为抗炎与抗癌药物的潜在治疗靶点。JAK抑制剂开发中的核心难题之一，是针对特定同工型的选择性问题；由于各JAK同工型序列同源性极高，实现选择性靶向颇具挑战。在各类JAKs中，主要表达于免疫细胞的贾努斯激酶3（Janus kinase 3, JAK3）是实现选择性靶向以提升治疗效果的最优同工型。本研究依托已知的JAK3-抑制剂复合物结构，采用基于结构的虚拟筛选方法，从PubChem数据库中筛选高亲和力JAK3抑制剂。通过严格的筛选标准（包括结构相似性、理化性质与分子相互作用等维度），本研究鉴定得到两种极具潜力的化合物：CID:68715657与CID:68585456，二者均展现出潜在的JAK3抑制活性。相较于母核分子，这两种化合物展现出更优的结合亲和力，且结构修饰亦优化了其与JAK3的相互作用，提示其具备更强的活性与选择性。分子动力学（Molecular dynamics, MD）模拟与分子力学-泊松玻尔兹曼表面积（MM-PBSA）分析证实，CID:68715657、CID:68585456与JAK3形成的复合物稳定性良好，进一步支持二者作为JAK3相关疾病治疗靶点的开发前景。但本研究仍存在局限：仅依赖计算预测未开展实验验证，且PubChem数据库在收录新型化学骨架方面存在一定限制。综上，本研究结果为将上述化合物优化为高效、高选择性JAK3抑制剂提供了坚实的理论基础。