Can Invalid Bioactives Undermine Natural Product-Based Drug Discovery?

High-throughput biology has contributed
a wealth of data on chemicals,
including natural products (NPs). Recently, attention was drawn to
certain, predominantly synthetic, compounds that are responsible for
disproportionate percentages of hits but are false actives. Spurious
bioassay interference led to their designation as pan-assay interference
compounds (PAINS). NPs lack comparable scrutiny,
which this study aims to rectify. Systematic mining of 80+ years of
the phytochemistry and biology literature, using the NAPRALERT database,
revealed that only 39 compounds represent the NPs most reported by
occurrence, activity, and distinct activity. Over 50% are not explained
by phenomena known for synthetic libraries, and all had manifold ascribed
bioactivities, designating them as invalid metabolic panaceas (IMPs). Cumulative
distributions of ∼200,000 NPs uncovered that NP research follows
power-law characteristics typical for behavioral phenomena. Projection
into occurrence–bioactivity–effort space produces the
hyperbolic black hole of NPs, where IMPs populate the high-effort
base.