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

Abstract

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.

Docking and Selectivity Studies of Covalently Bound Janus Kinase 3 Inhibitors

“…Previous studies on developing covalently bound JAK3 inhibitors have revealed that residues Lys855, Leu905, Pro906, Cys909, Asp912, and Arg953 are involved in ligand binding [ 19 , 20 , 21 , 22 , 23 , 26 , 28 ]. From the key residues in the multiple sequence alignment ( Figure S1 , Table 1 ), one can conclude that the most unique residue for selective JAK3 binding is cysteine 909.…”

“…Due to the highly conserved structural features of the ATP binding pocket, it has been challenging to achieve high selectivity among the JAK family. Many recent developments of JAK3 inhibitors have been focused on a JAK3 unique cysteine residue (CYS909) by forming a covalent bond with JAK3 inhibitors [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The idea of developing an inhibitor that can covalently bind to cysteine 909 was from other covalent drugs such as afatinib, osimertinib, and ibrutinib ( Figure 2 ).…”

“…Three drugs in Figure 2 shared a common α,β-unsaturated amide moiety to allow the Michael addition to the target protein via covalent binding. A number of JAK3 covalently bound inhibitors have been reported and some have been studied under various stages of clinical trials [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”