Distillation enables scalable high-fidelity virtual screening across ultra-large chemical libraries

Abstract

Accurate virtual screening of ultra-large chemical libraries remains challenging. Existing approaches rely on lower-fidelity scoring functions or sampling-based strategies that can limit predictive accuracy and bias the exploration of chemical space. Here, we present FastBindRank, a distillation-based framework that transfers the predictive power of the structure-based model Boltz-2 into an efficient sequence-based surrogate. Trained on [~]1% of the 122-million-compound PubChem library, FastBindRank enables high-fidelity screening at scale. Applied to histone deacetylase 11 (HDAC11), FastBindRank substantially enriched high-confidence binders relative to the background chemical space. The lightweight model captured structural patterns associated with predicted binding, revealing structural determinants of binding. Under a comparable computational budget, FastBindRank achieved a 74-fold increase in hit rate and over a 30-fold increase in discovery yield over direct subset-based screening. Experimental validation confirmed the activity of two novel compounds. These results establish distillation as a practical strategy for scalable, high-fidelity virtual screening of ultra-large chemical libraries.