Identification of Novel Small-Molecule Janus Kinase1 and 2 Inhibitors Through Structure-Based Virtual Screening, <i>In Vitro</i> Assays, and Molecular Dynamics Simulations
ACS OMEGA, vol.11, no.31, pp.46119-46135, 2026 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 11 Issue: 31
- Publication Date: 2026
- Doi Number: 10.1021/acsomega.6c02611
- Journal Name: ACS OMEGA
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Directory of Open Access Journals
- Page Numbers: pp.46119-46135
- Anadolu University Affiliated: Yes
Abstract
Janus kinases (JAKs) are central mediators of cytokine-driven signal transducer and activator of transcription (STAT) signaling, and dysregulation of the JAK-STAT axis is implicated in inflammatory, autoimmune, and neoplastic diseases. To identify new small-molecule inhibitors of Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2), we implemented an integrated virtual screening workflow combining structure-based docking and ligand-based prioritization using the InterBioScreen (IBS) compound library. A drug-likeness filter reduced 521,627 IBS molecules to 116,064 candidates, which were then docked into the ATP-binding sites of JAK1 (PDB ID: ) and JAK2 (PDB ID: ) using Glide SP; compounds were prioritized using docking score thresholds of <- 8.5 kcal/mol (JAK1) and <- 9.0 kcal/mol (JAK2), yielding 407 JAK1- and 298 JAK2-focused hits. Subsequent analysis shortlisted 42 candidates for enzymatic evaluation. In vitro kinase assays identified multiple nanomolar inhibitors, including compound 1-3 (IC50 = 0.032 mu M) among the most potent for JAK1 and compound 2-8 (IC50 = 0.026 mu M) for JAK2. Finally, 100 ns molecular dynamics (MD) simulations supported stable binding for representative complexes, with persistent hinge-region interactions for compound 1-3 in JAK1 (e.g., Glu957/Leu959) and compound 2-8 in JAK2 (e.g., Glu930/Leu932), consistent with a stable interaction network in the active site. Collectively, these results define validated IBS-derived hit scaffolds for further optimization and selectivity profiling toward JAK-targeted therapeutics.