FDB&FragLinker: A Large Fragment Database for Rapid Ligand Optimization Within Protein-Ligand Complex

Fragment-based drug design is a proven strategy for discovering high-quality leads. We present FDB&FragLinker, an integrated database and covalent optimization tool that enables users to explore, modify, and reassemble molecular fragments from DrugBank and a large subset of the ZINC database (800 M molecules). FragLinker is the first 3D complex generation tool based on fragement-level, allowing precise attachment of selected fragments onto small molecules at designated connection atoms via covalent docking, generating high-quality 3D protein-optimized ligand complex structures. This approach yields greater structural fidelity than traditional docking and is markedly faster than recent diffusion-based generative models. It can be widely applied to the optimization and modification of small molecules, PROTAC, small molecule polypeptides, etc. FDB&FragLinker is open-source and will be freely available via Webserver (https://hsadab.suat-sz.edu.cn/fdb/) and GitHub (https://github.com/guchengwanrenshan/FDB-FDBlinker).