Data_Sheet_1_Theoretical Exploring Selective-Binding Mechanisms of JAK3 by 3D-QSAR, Molecular Dynamics Simulation and Free Energy Calculation.docx

Janus kinase 3 (JAK3) plays a critical role in the JAK/STAT signaling pathway and has become an attractive selective target for the treatment of immune-mediated disorders. Therefore, great efforts have been made for the development of JAK3 inhibitors, but developing selective JAK3 inhibitors remains a great challenge because of the high sequence homology with other kinases. In order to reveal the selective-binding mechanisms of JAK3 and to find the key structural features that refer to specific JAK3 inhibition, a systematic computational method, including 3D-QSAR, molecular dynamics simulation, and free energy calculations, was carried out on a series of JAK3 isoform-selective inhibitors. Necessary pharmacodynamic structures and key residues involved in efficient JAK3-inhibition were then highlighted. Finally, 10 novel JAK3 inhibitors were designed, the satisfactory predicted binding affinity to JAK3 of these analogous demonstrated that this study may facilitate the rational design of novel and selective JAK3 inhibitors.

贾纳斯激酶3（Janus kinase 3, JAK3）在JAK-STAT信号通路中发挥关键作用，已成为治疗免疫介导性疾病的极具吸引力的选择性靶点。为此，学界已针对JAK3抑制剂的开发投入大量研究工作，但由于其与其他激酶的序列同源性较高，开发选择性JAK3抑制剂仍面临巨大挑战。为阐明JAK3的选择性结合机制，并挖掘与JAK3特异性抑制相关的关键结构特征，本研究针对一系列JAK3亚型选择性抑制剂，采用包括三维定量构效关系（3D-QSAR）、分子动力学模拟及自由能计算在内的系统性计算方法开展研究。随后，本研究明确了高效介导JAK3抑制所需的药效学结构与关键残基。最终，本研究设计得到10种新型JAK3抑制剂，经预测，这类化合物对JAK3均表现出令人满意的结合亲和力，表明本研究可为新型选择性JAK3抑制剂的合理设计提供有力助力。