Computational Design, Molecular Docking, SAR, and ADMET Analysis of Novel JAK1 Inhibitors as a Possible Treatment for Rheumatoid Arthritis

Vollständiger Abstract

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Rheumatoid arthritis is an inflammatory autoimmune disease affecting the joints which eventually leads to systemic comorbidities. Its pathogenesis was attributed to disturbances in the Janus Kinase/Signal Transducer and Activator of Transcription signaling pathway. In this research, an innovative lead compound C6 was created and docked toward Janus Kinase1 (JAK1). The docking process was confirmed by re-docking of the co-crystallized ligand MI1 (Tofacitinib). C6 showed a predicted docking score of -9.17 kcal/mol, with enhancement of 1.26 kcal/mol over Tofacitinib. Evaluation of the interactions showed a framework of five hydrogen bonds within the binding site involving an important contact with Glu966 as a residue selective for JAK1, offering a structural justification for the predicted isoform selectivity. A library of 11 analogs was designed rationally by three modification series. All molecules displayed a better predicted binding affinity than Tofacitinib and seven analogs were better than the lead compound. A2_3CF3 exhibited the most favorable predicted docking score. Structure-activity relationships analysis showed that the presence of electron-withdrawing groups at the meta position of the benzyl tail reduces the polar surface area and increases hydrophobic contacts, whereas ring contraction of the pyrrolidine linker to azetidine boosts the binding. Physicochemical assessment revealed that all compounds were found to obey Lipinski's rule of five, high expected gastrointestinal absorption, good oral bioavailability, and zero PAINS or Brenk structural alerts. Structural novelty examination showed maximum Tanimoto similarities below 0.115 to all five FDA approved JAK inhibitors. These results define the C6 scaffold as structurally distinct from available drugs and computationally potent JAK1 inhibitor.