Integrated Ligand and Structure based approaches towards developing novel Janus Kinase 2 inhibitors for the treatment of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are a group of diseases affecting hematopoiesis in humans. Types of MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and myelofibrosis. JAK2 gene mutation at 617th position act as a major causative factor for the onset and progression of MPNs. So, JAK2 inhibitors are widely used for the treatment of MPNs. But, increased incidence of adverse drug reactions associated with JAK2 inhibitors acts as a paramount challenge in the treatment of MPNs. Hence, there exists an urgent need for the identification of novel lead molecules with enhanced potency and bioavailability. We employed ligand and structure-based approaches to identify novel lead molecules which could act as JAK2 inhibitors. The dataset for QSAR modeling (ligand-based approach) comprised of 49 compounds. We have developed a QSAR model, which has got statistical as well as biological significance. Further, all the compounds in the dataset were subjected to molecular docking and bioavailability assessment studies. Derivative compounds with higher potency and bioavailability were identified for the best lead molecule present in the dataset by employing chemical space exploration. Dataset and models are available at https://github.com/giribio/agingdata O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/399907v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@130bdcaorg.highwire.dtl.DTLVardef@fc2de6org.highwire.dtl.DTLVardef@297758org.highwire.dtl.DTLVardef@5a41e0_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG