Molecular docking and dynamics in protein serine/threonine kinase drug discovery: advances, challenges, and future perspectives

Abstract

Protein serine/threonine kinases (STKs) regulate critical signaling pathways involved in cell growth, proliferation, metabolism, and apoptosis. Aberrant kinase activity is implicated in diverse human diseases, including cancer, neurodegeneration, and inflammatory disorders. Structure-based drug discovery, utilizing molecular docking and molecular dynamics (MD) simulations, has become a central strategy for identifying and optimizing STK inhibitors. In this review, we summarize recent advances and challenges in applying these in silico approaches to STK drug discovery. We discuss the principles, performance, and limitations of docking and MD approaches, as well as their integration with binding free-energy estimation methods. We emphasize recent methodological progress, including automated MD workflows, machine learning-driven interaction fingerprinting frameworks, and the growing adoption of hybrid docking-MD pipelines that enhance throughput and reproducibility. The review also highlights emerging directions such as computational design of heterobifunctional degraders (PROTACs) and allosteric modulators, which extend the scope of kinase targeting beyond ATP-competitive inhibitors. Quantitative examples of computational resource requirements and hit-validation rates from representative studies are summarized to contextualize the predictive power and practical feasibility of these approaches. Together, these developments demonstrate how the synergy of physics-based simulations, enhanced sampling, and machine learning is transforming MD from a purely descriptive technique into a scalable, quantitative component of modern kinase drug discovery.