Focus on PAINS: false friends in the quest for selective anti-protozoal lead structures from Nature?

Pan-assay interference compounds (PAINS) are molecules showing promising but deceptive activities in various biochemical screenings mainly due to unselective interactions with the target. Overall awareness of this problem has been raised recently. Many natural products inherently have PAINS characteristics but are nevertheless uncritically acclaimed as new antiprotozoal lead structures. However, a non-selective mode of action may be the cause of observed activity. This review describes the most common assay-interfering characteristics of antiprotozoal natural products, discusses significant examples from the recent literature and strategies to deal with these promiscuous structures. Pan-assay interference compounds (PAINS) are molecules showing promising but deceptive activities in various biochemical screenings mainly due to unselective interactions with the target.