We have developed the Pocket Crafter workflow to carry out virtual hit identification in early drug discovery using a 3D generative chemistry approach. As a case study, the Pocket Crafter workflow has facilitated the hit identification for the WDR5 WBM pocket successfully, with a higher hit rate compared with the experimental HTRF screening results. The biological activity of these hits has been validated through in vitro assays, confirming their role as genuine WDR5 binders and disruptors of the WDR5-MYC interaction. The discovery of this new chemical series marks a promising starting point for WDR5 drug development. Through the efficient exploration of a vast chemical space and the incorporation of pertinent structural information, we have showcased the significant potential and efficacy of this workflow in expediting the identification of potential drug candidates. This approach opens up new avenues for the development of innovative therapies to address unmet medical needs, offering expanded possibilities in the field of drug discovery.