Combination of ligand‑based and structure‑based virtual screening for the discovery of novel Janus kinase 2 inhibitors against philadelphia-negative myeloproliferative neoplasms.

Abstract

The activating V617F mutation in Janus kinase 2 (JAK2) has been shown to be the major cause for classic Philadelphia-negative myeloproliferative neoplasms (MPNs). Thus, the development of pharmacologic JAK2 inhibitors is an essential move in combating MPNs. In this study, screening methods examining both ligands and their structures were developed to discover novel JAK2 inhibitors from the ChemDiv database with virtual screening identifying 886 candidate inhibitors. Next, these compounds were further filtered using ADMET, drug likeliness, and PAINS filtering, which reduced the compound number even further. This consolidated list of candidate compounds (n = 49) was then evaluated biologically at molecular level and the highest performing inhibitor with a novel scaffold was selected for further examination. This candidate inhibitor, CD4, was then subjected to molecular dynamics studies, with complex stability, root-mean-square deviation, radius of gyration, binding free energy, and binding properties all examined. The result suggested that CD4 interacts with JAK2 and that the CD4-JAK2 complex is stable. This study was able to identify a candidate inhibitor that warrants further examination and optimization and may potentially serve as a future MPN treatment.