Abstract
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.
Highlights
Cytokines play important roles in multiple cellular functions, such as cell proliferation, invasion, survival, inflammation, and immunity
The bio-affinities of these inhibitors cover a range of 4 orders of a magnitude and are evenly distributed over this range. These molecules were constructed based on the structure of compound 61 (Cpd61) retrieved from the co-crystallized structure of the Cpd61/Janus kinase 3 (JAK3) complex (PDB ID: 3ZC6), and optimized with MMFF94 force filed in SYBYL-X2.0
Several CoMFA models were generated upon a series of 56 pyrrolopyrazine derivatives and the results are summarized in Supplementary Table S2
Summary
Cytokines play important roles in multiple cellular functions, such as cell proliferation, invasion, survival, inflammation, and immunity. The JAK family is a class of non-receptor tyrosine kinases and can be divided into four members, JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2) They act as hubs during the signaling transduction process for multiple cytokines (Imada and Leonard, 2000; Leonard and Lin, 2000; Shuai and Liu, 2003), and depicts JAKs as attractive targets of immunosuppression. PF-06651600 displays the most salient selectivity due to the covalent, irreversible interaction with the Cys909 of JAK3, which is a unique residue within the JAK family (Farmer et al, 2015; Thorarensen et al, 2017; Hamaguchi et al, 2018), and at present, it is a mainstream approach in the design of JAK3 selective inhibitors Another approach is to develop ATP-competitive inhibitors with reversible binding interactions with specific regions in JAK3. 10 new JAK3 inhibitors were designed according to the simulation results and the inhibitor with the best-predicted potency was taken as a reference to investigate the JAK3-inhibiting selectivity
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