Pharmacophore filtering and 3D-QSAR in the discovery of new JAK2 inhibitors

Janus kinase 2 (JAK2) plays a crucial role in the patho-mechanism of cardiovascular pathologies, myeloproliferative disorders and many other diseases. Thus, effective JAK2 kinase inhibitors may be of significant therapeutic importance. In this study, a pharmacophore mapping studies were undertaken for a series of phenylaminopyrimidines derivatives. A five point pharmacophore with two hydrogen bond donors (D), two hydrogen bond acceptors (A) and one aromatic ring (R) as pharmacophoric features were developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R2 = 0.970 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of Q2 = 0.822. The external validation indicated that our QSAR models possessed high predictive powers with r02 value of 0.999 and rm2 value of 0.637 respectively. The model was then employed as 3D search query to screen against public compound libraries (Asinex, TOSLab, Maybride and Binding database) in-order to identify a new scaffold. We have identified thirteen distinct drug-like molecules binding to the JAK2. Interestingly, some of the compounds show activity against JAK2 by PASS biological activity prediction. Hence, these molecules could be potential selective inhibitors of JAK2 that can be experimentally validated and their backbone structural scaffold could serve as building blocks in designing drug-like molecules for JAK2.

Graphical abstract. Atom based 3D-QSAR study of phenylaminopyrimidines derivatives suggest that substitution of N-(cyanomethy) formamide and thiomorpholine to the 4-phenyl-N-[4-(piperidin-1-yl)phenyl]pyrimidin-2-amine scaffold will enhance the activity and pharmacokinetic property of the compound. The pharmacophore model was employed as 3D search query to screen against public compound libraries. The pharmacophore captured more than 1000 hits which were filtered by three docking runs, identifying 13 hits.Figure optionsDownload full-size imageDownload high-quality image (266 K)Download as PowerPoint slideHighlights► Atom based 3D-QSAR study of phenylaminopyrimidines derivatives was derived to find features which are responsible for biological activity as selective JAK2 inhibitors. ► The pharmacophore model was employed as 3D search query to screen against public compound libraries (Asinex, TOSLab, Maybride and Binding database). ► The pharmacophore captured more than 1000 hits which were filtered by three docking runs, identifying 13 hits which were subjected to Biological activity prediction by PASS.