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πŸ“• Can Invalid Bioactives Undermine Natural-Product Based Drug Discovery


Tags: IMPs PAINS HTS false hit news
Bisson J, McAlpine JB, Friesen JB, Chen S, Graham J, Pauli GF
Journal of Medicinal Chemistry 59(5), 1671-1690 (2015)
DOI:10.1021/acs.jmedchem.5b01009
PMC:PMC4791574 [OpenAccess]

Abstract

TOC graphic of the imp paper

High-throughput biology contributed a wealth of data on chemicals including natural products (NPs). Recently, attention was drawn to certain predominantly synthetic compounds which are responsible for disproportionate percentages of hits but β€œfalse” actives. Spurious bioassay interference designated them as pan-assay interference compounds (PAINS). NPs lack comparable scrutiny, which this study aims to rectify. Systematic mining 80+-years of the phytochemistry and biology literature, using the NAPRALERT database, revealed that only 39 compounds cover 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. Awareness of IMPs helps clearing the path to meaningful drug leads.