The article discusses the problem of "PAINS" (pan-assay interference compounds) in drug discovery. These are molecules that can falsely appear active in multiple assays, misleading researchers and wasting time and resources. PAINS often have reactive properties that cause false signals in various tests, such as producing hydrogen peroxide or reacting with proteins in non-specific ways. They can also interfere with the function of proteins or sequester essential metal ions, making it difficult to determine if a compound is truly effective. The article highlights that many compounds identified as "hits" in drug screens are actually PAINS. These compounds are often reported as having promising activity against a wide range of proteins, leading to unnecessary research and development efforts. Some well-known PAINS include toxoflavin, curcumin, and rhodanines, which are known for their promiscuous actions and have been used as drug leads despite their potential to interfere with assays. The authors suggest several strategies to avoid PAINS in drug discovery. These include learning to recognize disreputable structures, checking the literature for similar compounds, and assessing assays with different readouts. They also recommend verifying the identity and purity of compounds and being cautious of molecules that show strong activity in screening but may not be effective in cells. The article emphasizes the importance of vigilance in academic drug discovery and the need for better awareness of PAINS to prevent wasted efforts. It also calls for the inclusion of computer-readable molecular structures in scientific publications to aid in the identification of PAINS. The authors conclude that PAINS hits should be ignored, as they are unlikely to lead to successful drug development.The article discusses the problem of "PAINS" (pan-assay interference compounds) in drug discovery. These are molecules that can falsely appear active in multiple assays, misleading researchers and wasting time and resources. PAINS often have reactive properties that cause false signals in various tests, such as producing hydrogen peroxide or reacting with proteins in non-specific ways. They can also interfere with the function of proteins or sequester essential metal ions, making it difficult to determine if a compound is truly effective. The article highlights that many compounds identified as "hits" in drug screens are actually PAINS. These compounds are often reported as having promising activity against a wide range of proteins, leading to unnecessary research and development efforts. Some well-known PAINS include toxoflavin, curcumin, and rhodanines, which are known for their promiscuous actions and have been used as drug leads despite their potential to interfere with assays. The authors suggest several strategies to avoid PAINS in drug discovery. These include learning to recognize disreputable structures, checking the literature for similar compounds, and assessing assays with different readouts. They also recommend verifying the identity and purity of compounds and being cautious of molecules that show strong activity in screening but may not be effective in cells. The article emphasizes the importance of vigilance in academic drug discovery and the need for better awareness of PAINS to prevent wasted efforts. It also calls for the inclusion of computer-readable molecular structures in scientific publications to aid in the identification of PAINS. The authors conclude that PAINS hits should be ignored, as they are unlikely to lead to successful drug development.