This study presents a comprehensive approach to designing and optimizing small molecule inhibitors targeting Salt-Inducible Kinases 2 and 3 (SIK2 and SIK3), crucial regulators of cellular signaling pathways implicated in various diseases, including cancer, inflammation, and metabolic disorders. By integrating advanced computational methods and expert-driven chemical synthesis, we generated a diverse library of potential inhibitors and meticulously evaluated their pharmacological properties and binding affinities to SIK2.

Through a rigorous analysis of generated data and molecular docking simulations, we successfully identified lead compounds with promising therapeutic potential. Subsequently, employing iterative chemical modifications guided by human expertise, we further optimized these leads, enhancing their efficacy and specificity. Additionally, employing molecular dynamics simulations provided valuable mechanistic insights into the dynamic behavior of optimized compounds within the complex biological environment, elucidating their potential as effective inhibitors of SIK2 activity.

Our findings underscore the efficacy and significance of an integrated computational and experimental approach in the development of novel therapeutics targeting SIK2 and SIK3. By bridging computational predictions with experimental validation, this approach not only accelerates the drug discovery process but also increases the likelihood of identifying clinically relevant compounds. Furthermore, the insights gained from this study lay a solid foundation for future preclinical and clinical investigations, paving the way for the development of effective treatments for diseases associated with dysregulated SIK2 and SIK3 signaling pathways.