"Design of Rational JAK3 Inhibitors Based on the Parent Core Structure of 1,7-Dihydro-Dipyrrolo [2,3-b:3 ',2 '-e] Pyridine"

作者全名："Li, Yihao; Meng, Dan; Xie, Jiali; Li, Ruoyu; Wang, Zifan; Li, Jinlong; Mou, Lin; Deng, Xinhao; Deng, Ping"

作者地址："[Li, Yihao; Meng, Dan; Xie, Jiali; Li, Ruoyu; Wang, Zifan; Li, Jinlong; Mou, Lin; Deng, Xinhao; Deng, Ping] Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China; [Meng, Dan; Xie, Jiali; Li, Ruoyu; Deng, Ping] Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China; [Meng, Dan; Xie, Jiali; Li, Ruoyu; Deng, Ping] Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing 400016, Peoples R China"

通信作者："Deng, P (通讯作者)，Chongqing Med Univ, Coll Pharm, Chongqing 400016, Peoples R China.; Deng, P (通讯作者)，Chongqing Res Ctr Pharmaceut Engn, Chongqing 400016, Peoples R China.; Deng, P (通讯作者)，Chongqing Key Res Lab Qual Evaluat & Safety Res A, Chongqing 400016, Peoples R China."

来源：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

ESI学科分类：CHEMISTRY

WOS号：WOS:000803670500001

JCR分区：Q2

影响因子：5.6

年份：2022

卷号：23

期号：10

开始页：　

结束页：　

文献类型：Article

关键词：JAK3; parent structure design; backbone growth; molecular docking; molecular dynamics

摘要："JAK3 differs from other JAK family members in terms of tissue distribution and functional properties, making it a promising target for autoimmune disease treatment. However, due to the high homology of these family members, targeting JAK3 selectively is difficult. As a result, exploiting small changes or selectively boosting affinity within the ATP binding region to produce new tailored inhibitors of JAK3 is extremely beneficial. PubChem CID 137321159 was used as the lead inhibitor in this study to preserve the characteristic structure and to collocate it with the redesigned new parent core structure, from which a series of 1,7-dihydro-dipyrrolo [2,3-b:3 ',2 '-e] pyridine derivatives were obtained using the backbone growth method. From the proposed compounds, 14 inhibitors of JAK3 were found based on the docking scoring evaluation. The RMSD and MM/PBSA methods of molecular dynamics simulations were also used to confirm the stable nature of this series of complex systems, and the weak protein-ligand interactions during the dynamics were graphically evaluated and further investigated. The results demonstrated that the new parent core structure fully occupied the hydrophobic cavity, enhanced the interactions of residues LEU828, VAL836, LYS855, GLU903, LEU905 and LEU956, and maintained the structural stability. Apart from this, the results of the analysis show that the binding efficiency of the designed inhibitors of JAK3 is mainly achieved by electrostatic and VDW interactions and the order of the binding free energy with JAK3 is: 8 (-70.286 kJ/mol) > 11 (-64.523 kJ/mol) > 6 (-51.225 kJ/mol) > 17 (-42.822 kJ/mol) > 10 (-40.975 kJ/mol) > 19 (-39.754 kJ/mol). This study may provide a valuable reference for the discovery of novel JAK3 inhibitors for those patients with immune diseases."

基金机构：Fundamental and Advanced Research Projects of Chongqing City [cstc2019jcyj msxmX0034]

基金资助正文：This research was funded by the Fundamental and Advanced Research Projects of Chongqing City (cstc2019jcyj msxmX0034).