In summary, developing QSAR models that prioritize higher PPV without relying on dataset balancing aligns more closely with HTVS goals. This study's insights not only challenge conventional QSAR modeling practices but also provide a clearer pathway for the identification of active compounds, advocating for a strategic redirection in early-stage hit discovery. As cheminformatics continues to evolve, embracing methodologies that directly address the needs of modern drug discovery will undoubtedly pave the way for more efficient and costeffective screening processes. Furthermore, we posit that approaches considered and advocated for in this contribution should find broader use in the domain of information retrieval, where early enrichment is often a primary goal . Information retrieval spans a diverse spectrum of fields including chemistry , medicine , genomics , and even music . Thus, more robust approaches for assessing and building models for early enrichment tasks can result in benefits to all these areas.