In-silico Studies of Thiophene-2-carboxamide Derivatives as Inhibitors of the SH2 Domain of Interleukin-2-Inducible T-Cell Kinase (ITK)

The interleukin-2-inducible T-cell kinase (ITK) is a key mediator of T-cell signaling, with its SH2 domain implicated in cancer and autoimmune pathologies, making it a promising therapeutic target. This study employs in-silico techniques to evaluate the potential of thiophene-2-carboxamide derivatives as inhibitors of the SH2 domain of interleukin‑2‑inducible T‑cell kinase (ITK). A dataset of 69 compounds was subjected to molecular docking against the SH2 domain of Interleukin-2-inducible T-cell kinase (ITK) (PDB ID: 1LUI) to identify high-affinity binders. The top three compounds, CMP2, CMP9, and CMP33, demonstrated ICM docking scores of -37.774, -37.580, and -37.668, respectively, used for rank-ordering compounds. Structure-based drug design strategies led to the design of novel derivatives (CMP2b, CMP9a, and CMP33a), which showed improved ICM docking scores and favorable drug-likeness properties. Molecular dynamics simulations confirmed the stability of these lead compounds within the receptor binding site, while ADMET predictions suggested promising pharmacokinetic profiles. The findings highlight CMP2b, CMP9a, and CMP33a as promising candidates for further experimental validation and optimization as potential inhibitors of ITK pending experimental confirmation of inhibitory activity.