Molecular modeling studies of pyrrolo[2,3-d]pyrimidin-4-amine derivatives as JAK1 inhibitors based on 3D-QSAR, molecular docking, molecular dynamics (MD) and MM-PBSA calculations.

Rheumatoid Arthritis (RA) is an autoimmune disease caused by overproduction of pro-inflammatory cytokines. Janus Kinases (JAKs) mediate cytokines signaling through the Janus Kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. Clinical studies have shown that Janus kinase 1 (JAK1) mediated signaling plays a key role in synovial response in rheumatoid arthritis. Hence, the inhibition JAK1 is considered as an important therapeutic route for treatment of rheumatoid arthritis. In this study, we have performed three-dimensional quantitative structure-activity relationship (3 D-QSAR), molecular docking, molecular dynamics (MD) and free energy calculations on a series of pyrrolo[2,3-d]pyrimidin-4-amine JAK1 inhibitors. Molecular docking studies of the compounds 03, 13, 36 and 49 with JAK1 were performed to study the binding interactions. The binding conformations of the compounds from docking studies were selected based on binding energy and H-bond interactions and were used as initial structure for MD simulations. Using 3 D-QSAR techniques, a ligand-based comparative molecular field analysis (CoMFA) model (q2 = 0.5, r2 = 0.96) and a receptor-based CoMFA model (q2 = 0.78, r2 = 0.98) were developed. Analysis of the MD results of the most active compound (compound 49) with JAK1 showed the formation of H-bond interactions with residues Glu957, Leu959 and Gly887 and water-mediated H-bond interaction with Gly887 and His885. Based on the contour map analyses of the receptor-based CoMFA, a design strategy was proposed and was used for designing new JAK1 inhibitors. Four of the designed compounds (D57, D58, D98 and D99) showed predicted activity values (pIC50> 8.8) greater than the most active compound for JAK1. MM-PBSA based free energy calculations indicated that the designed compounds were able to form stable binding with JAK1 primarily through electrostatic interactions and van der Waal interactions. Collectively, the outcome of this study can be used to further the progress of JAK1 inhibition for the treatment of rheumatoid arthritis. Communicated by Ramaswamy H. Sarma.