a (College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China)
b (School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China)
Molecular Docking, 3D-QSAR and Molecular Dynamics Simulation Studies of Substituted Pyrimidines as Selective Covalent Janus Kinase 3 Inhibitors
CAI Xiao-Li;MA Yu-Zhuo;ZHAO Zhong-Xiang;ZHANG Ling;LIU Ying-Xiang
a (College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China)
b (School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China)
Abstract：Janus kinase 3 (JAK3) is a member of Janus kinase (JAK) family, and it represents a promising target for the treatment of immune diseases and cancers. However, no highly selective inhibitors of JAK3 have been developed. For discovering the binding mechanism of JAK3 and these inhibitors, a molecular modeling study combining molecular docking, three-dimensional quantitative structure-activity relationships (3D-QSAR), molecular dynamics and binding free energy calculations was performed on a series of pyrimidine-based compounds which could bind with the unique residue Cys909 of JAK3 kinase as the selective inhibitors of JAK3 in this work. The optimum CoMFA and CoMSIA models were generated based on the conformations obtained by molecular docking. The results showed that the models have satisfactory predicted capacity in both internal and external validation. Furthermore, a 50 ns molecular dynamics simulation was carried out to determine the detailed binding process of inhibitors with different activities. It was demonstrated that hydrogen bond interactions with Leu828, Glu903, Tyr904, Leu905 and Leu956 of JAK3 are significant for activity increase, and the Van der Waals interaction is mainly responsible for stable complex.
This work was supported by the National Natural Science Foundation of China (No 81270054) and the program for Outstanding Young Teachers in Higher Education Institutions of Guangdong Province (No. Yq2013045)
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