Golani, L. K. | Search bioRxiv

bioRxiv2026

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

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.

bioinformatics↗

bioRxiv2019

Non-sedating benzodiazepines cause contractile paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports of cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines, given the known anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970s but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZs anti-parasitic target is likely distinct from the human receptors that drive sedation. Therefore, we screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, causing extensive vacuole formation beneath the apical membrane. The imidazobenzodiazepine compound series identified has a dramatically lower ([~]1 log) affinity for human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects.\n\nAuthor SummaryOver 200 million people are infected with schistosomiasis, yet there are limited therapeutic options available to treat this disease. The benzodiazepine meclonazepam is known to cure both intestinal and urinary schistosomiasis in animal and human studies, but dose-limiting sedation has been a barrier to its development. Little is known about the structure-activity relationship of meclonazepam and other benzodiazepines on schistosomes, or the identity of the parasite receptor for these compounds. However, schistosomes lack obvious homologs to the human GABAARs that cause sedation. This indicates that the parasite target of this drug is distinct from the host receptors that underpin dose-limiting side effects of meclonazepam, and raises the possibility that benzodiazepines with poor GABAAR affinity may still retain anti-parasitic effects. Here, we report an in vitro screen of various benzodiazepines against schistosomes, and the identification of hit compounds that are active against worms yet possess reduced affinity for the human GABAARs that cause sedation.

pharmacology and toxicology↗