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Janus kinases (JAKs) are a family of non-receptor kinases that play a key role in cytokine signaling and their aberrant activities are associated with the pathogenesis of various immune diseases. The JAK1 isoform plays an essential role in the types 1 and II interferon signaling and elicits signals from the interleukin-2, interleukin-4, gp130, and class 2 receptor families. It is ubiquitously expressed in humans and its overexpression has been linked with autoimmune diseases such as myeloproliferative neoplasm. Although JAK1 inhibitors such as Tofacitinib have been approved for medical use, the low potency and off-target effects of these inhibitors have limited their use and calls for the development of novel JAK1 inhibitors. In this study, we used computational methods on a series of pyrrolopyridine derivatives to design new JAK1 inhibitors. Molecular docking and molecular dynamics simulation methods were used to study the protein-inhibitor interactions. 3D-quantitative structure–activity relationship models were developed and were used to predict the activity of newly designed compounds. Free energy calculation methods were used to study the binding affinity of the inhibitors with JAK1. Of the designed compounds, seventeen of the compounds showed a higher binding energy value than the most active compound in the dataset and at least six of the compounds showed higher binding energy value than the pan JAK inhibitor Tofacitinib. The findings made in this study could be utilized for the further development of JAK1 inhibitors.

The G-protein coupled receptor kinase 2 (GRK2) regulates the desensitization of beta-adrenergic receptors (β-AR), and its overexpression has been implicated in heart failure. Hence, the inhibition of GRK2 is considered to be an important drug target for the treatment of heart failure. Due to the high sequence similarity of GRK2 with the A, G, and C family (AGC family) of kinases, the inhibition of GRK2 also leads to the inhibition of AGC kinases such as Rho-associated coiled-coil kinase 1 (ROCK1). Therefore, unraveling the mechanisms to selectively inhibit GRK2 poses an important challenge. We have performed molecular docking, three dimensional quantitative structure activity relationship (3D-QSAR), molecular dynamics (MD) simulation, and free energy calculations techniques on a series of 53 paroxetine-like compounds to understand the structural properties desirable for enhancing the inhibitory activity for GRK2 with selectivity over ROCK1. The formation of stable hydrogen bond interactions with the residues Phe202 and Lys220 of GRK2 seems to be important for selective inhibition of GRK2. Electropositive substituents at the piperidine ring and electronegative substituents near the amide linker between the benzene ring and pyrazole ring showed a higher inhibitory preference for GRK2 over ROCK1. This study may be used in designing more potent and selective GRK2 inhibitors for therapeutic intervention of heart failure.