Abstract
Background: Janus kinase 2 (JAK2) is a significant enzyme, which plays an essential role in myeloproliferative disorders (MPDs) and many other diseases. Inhibition of JAK2 activity by small molecule inhibitors has been attracting a great deal of MPDs and cancer therapy. Method: Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 30 compounds belonging to 2,4-diamino-1,3,5-triazine derivatives for potent JAK2 inhibitory activity. The data set of the compounds was also docked into the binding site of JAK2 using GLIDE and the active residues of the binding site were analyzed. A five-point pharmacophore model AADDH, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one hydrophobic region (H) was developed by PHASE module of Schrödinger suite Maestro 9. Results: The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (R2 = 0.96, SD = 0.21, F = 124.5, N = 24) and test set (Q2 = 0.76, RMSE = 0.44, Pearson R = 0.87, N = 6) molecules. It was found that the most active compound 19 interacted with the active residues namely Leu932 (2), Arg980, Leu855 (Glide score = -7.37), whereas the reference compound Ruxolitinib interacted with the active residues, Leu932, Glu930 (Glide score = -9.26). Conclusion: The above 3D-QSAR model illustrates that electron-withdrawing and hydrophobic groups might prove efficacious for JAK2 inhibitory activity as evident from the docking results, which clearly show the hydrogen bond interactions with the active residues of these compounds. Thus, it is contemplated that the substitution of methoxy, phenoxy, morpholinoacetamide, oxyalkyl & oxyaryl groups on 2,4-diamino-1,3,5-triazine scaffold might increase the activity of the compounds against JAK2 protein. The above result provides an insight for further design and development of newer chemical entities as JAK2 inhibitors.
