Pharmacophore generation and atom-based 3D-QSAR analysis of substituted aromatic bicyclic compounds containing pyrimidine and pyridine rings as Janus kinase 2 (JAK2) inhibitors

Rajasekhar Chekkara, E. Susith

Abstract

Janus kinase 2 plays a critical role in JAK/STAT signaling pathways, and has a central role in cell cycle. JAK2 have emerged as a novel therapeutic target of myeloproliferative disorders, autoimmune diseases, essential thrombocytosis, and small molecular inhibition of JAK2 activity developed into an impressive drug target. For a series of JAK2 inhibitors pharmacophore model and atom-based 3D-QSAR models have been developed, to identify the essential structural features required for these JAK2 inhibitors using the PHASE module of Schrodinger. A five featured pharmacophore hypothesis with three hydrogen bond acceptors, one hydrogen bond donor and one aromatic ring provided a best atom-based 3D-QSAR model. The developed 3D-QSAR model have good statistical predictive values as R2 = 9659, Q2 = 0.5679 and effective Pearson R = 0.9405. The results illustrate the structural information of substituted aromatic bicyclic compounds containing pyrimidine and pyridine rings, which might be supportive for further rational design of novel potent Janus kinase 2 inhibitors.