Current status and prospects of molecular docking in PET probe development

Positron emission tomography (PET) is an advanced imaging modality that enables visualization of molecular and cellular processes, with PET probes serving as its critical core component. Molecular docking is a computational technique that predicts binding modes and interactions between ligands and their biological targets. Driven by breakthroughs in structural biology and computational technology, molecular docking has evolved into an indispensable auxiliary tool for modern PET probe development. This review introduces the fundamental principles of molecular docking, including core algorithms, scoring functions, and commonly used software packages. It then comprehensively examines its applications across the entire PET probe development pipeline: virtual screening for lead compound discovery; rational structural optimization along three complementary dimensions (reinforcing favorable interactions, eliminating unfavorable factors, and rational design of radiolabeling sites); and widespread retrospective analysis of binding modes. Furthermore, it addresses the application of molecular docking in systematic evaluation of existing probes, with a focus on tau-targeted tracers, where it has been used to compare binding sites, subtype selectivity, and off-target mechanisms across multiple probes and distinct tau fibril isoforms. This review illustrates the utility of molecular docking as a comprehensive tool in PET probe development. Although current applications remain predominantly retrospective analysis, with continuous breakthroughs and deep integration of technologies such as high‑precision structure prediction and GPU‑accelerated ultra‑large‑scale screening, molecular docking is poised to become a key enabler for the rational development of PET probes.