Pharmacophore modeling and 3D-QSAR studies of 2,4-disubstituted pyrimidine derivatives as Janus kinase 3 inhibitors

Abstract

A robust pharmacophore model was developed and the structure-activity relationship was analyzed using 71 pyrimidine derivatives reported for covalent Janus Kinase 3 (JAK3) inhibition. Pharmacophore modeling developed a five featured pharmacophore: one H-bond acceptor, two H-bond donors, one hydrophobic, and one aromatic ring features. The atom-based three-dimensional QSAR models with statistical significance were generated using the training set of 52 compounds. The excellent predictive correlation coefficients were obtained for 3D models determined using a test set of 19 molecules. The generated QSAR model implies that the hydrophobic character is important for the JAK3 inhibitory activity of these compounds. Additionally, electron-withdrawing and hydrogen bond donor groups at specific positions positively contribute to the JAK3 inhibition potency. These results provided essential three-dimensional structural requirements and the crucial binding features of 2,4-disubstituted pyrimidine derivatives, which may direct for the design and discovery of novel potent JAK3 inhibitors.