Virtual Screening for the Discovery of Microbiome β‑Glucuronidase Inhibitors to Alleviate Cancer Drug Toxicity

Despite
the potency of most first-line anti-cancer drugs, nonadherence
to these drug regimens remains high and is attributable to the prevalence
of “off-target” drug effects that result in serious
adverse events (SAEs) like hair loss, nausea, vomiting, and diarrhea.
Some anti-cancer drugs are converted by liver uridine 5′-diphospho-glucuronosyltransferases
through homeostatic host metabolism to form drug-glucuronide conjugates.
These sugar-conjugated metabolites are generally inactive and can
be safely excreted via the biliary system into the
gastrointestinal tract. However, β-glucuronidase (βGUS)
enzymes expressed by commensal gut bacteria can remove the glucuronic
acid moiety, producing the reactivated drug and triggering dose-limiting
side effects. Small-molecule βGUS inhibitors may reduce this
drug-induced gut toxicity, allowing patients to complete their full
course of treatment. Herein, we report the discovery of novel chemical
series of βGUS inhibitors by structure-based virtual high-throughput
screening (vHTS). We developed homology models for βGUS and
applied them to large-scale vHTS against nearly 400,000 compounds
within the chemical libraries of the National Center for Advancing
Translational Sciences at the National Institutes of Health. From
the vHTS results, we cherry-picked 291 compounds via a multifactor prioritization procedure, providing 69 diverse compounds
that exhibited positive inhibitory activity in a follow-up βGUS
biochemical assay in vitro. Our findings correspond
to a hit rate of 24% and could inform the successful downstream development
of a therapeutic adjunct that targets the human microbiome to prevent
SAEs associated with first-line, standard-of-care anti-cancer drugs.