PROTAC-DB 4.0: an expanded knowledgebase of targeted protein degradation modalities with AI-powered knowledge discovery

Proteolysis-targeting chimeras (PROTACs) represent an emerging therapeutic modality that harnesses the ubiquitin-proteasome system to induce targeted protein degradation (TPD). Their event-driven and catalytic mechanisms provide new opportunities to target previously undruggable proteins. However, the rapid expansion of TPD technologies, including molecular glues (MGs) and X-functional targeting chimeras (XTACs), together with the increasing application of artificial intelligence (AI) in degrader design, highlights the need for comprehensive and continuously updated data resources. Here, we present PROTAC-DB 4.0, an expanded knowledgebase covering major targeted degradation and induced-proximity technologies. Compared with the previous version, PROTAC-DB 4.0 contains 15 502 PROTAC entries, together with 24 798 MG entries and 272 XTAC entries, with expanded experimental annotations, patent-derived compounds, and modality-specific data fields. A major advancement in PROTAC-DB 4.0 is the integration of a large language model and retrieval-augmented generation-based natural language query system, which connects structured database records with scientific literature to enable intuitive knowledge discovery across PROTACs, MGs, and XTACs. By combining comprehensive data curation with AI-assisted information retrieval, PROTAC-DB 4.0 provides an accessible platform to support degrader discovery, data-driven modeling, and rational design of next-generation targeted degradation and induced-proximity therapeutics. PROTAC-DB 4.0 is freely accessible at http://cadd.zju.edu.cn/protacdb/.