Design and Screening Research of Novel TYK2 Inhibitors Based on QSAR, Molecular Docking, and Molecular Dynamics Simulation

Abstract

Tyrosine kinase 2 (TYK2) is an important target for the treatment of inflammatory bowel disease and plays a key role in cytokine signal transduction. This study took 52 novel selective TYK2 inhibitors with anti-inflammatory activity as the dataset and systematically constructed four QSAR models: CoMFA, CoMSIA, Topomer CoMFA, and HQSAR. These models demonstrated excellent fitting and predictive capabilities through both internal cross-validation and external test set validation. Based on the QSAR results combined with screening from the ZINC20 database, 16 new compounds with high predicted activity were designed. Furthermore, molecular docking and molecular dynamics simulations were performed to verify the stable binding characteristics of these compounds to the target protein. This study not only provided an effective screening tool for the design of novel TYK2 inhibitors but also proposed a series of potential candidate molecules, which may offer valuable references for optimizing the pharmacokinetic properties and overcoming drug resistance issues of TYK2 inhibitors, thereby facilitating their clinical application.