Computational insights into insect-derived semiochemicals from Formicidae family as potential JAK1 inhibitors:...

JAK1 is a crucial pharmacological target for treating various inflammatory disorders. Although current JAK inhibitors are effective, they come with significant long-term adverse effects. This prioritises the challenge of developing safer novel JAK inhibitors. Nature presents an extensive array of bioactive compounds, and the vast diversity found within insects constitutes a rich repository for chemical exploration and discovery. This study conducted a virtual screening of the inhibitory effects of semiochemicals derived from insects belonging to the Formicidae (ant) family, sourced from the Pherobase Library, against the human JAK1 target protein co-crystallised with Abrocitinib, a standard inhibitor. The investigation utilized site-specific molecular docking techniques, followed by ADMET profiling and molecular dynamics simulation to assess the interactions and stability of the compounds. This study identified promising compounds exhibiting high binding affinities against the kinase domain of JAK1. A total of 1319 compounds were evaluated, of which six exhibited significant binding affinity and satisfied the requisite ADMET criteria. The two selected compounds, 3-Methyl-4-phenylpyrrole and Methyl 3-indoleacetate with binding affinities -10.1 and -9.0 Kcal/mol respectively were further evaluated via molecular dynamic simulation studies to estimate protein-ligand complex stability. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculation showed that 3-methyl-4-phenylpyrrole (ΔG_bind = -48,280.465 kJ/mol) exhibited the strongest binding affinity to the target, surpassing that of Abrocitinib, while methyl 3-indoleacetate demonstrated relatively weak interaction. This extensive computational analysis highlights the potential of insect-derived semiochemical compounds as innovative JAK1 inhibitors for modulating various pro-inflammatory cytokines. However, these results necessitate experimental validation for confirmation.