Compounds that selectively modulate multiple targets can provide clinical benefits and are an alternative to traditional highly selective agents for unique targets.High-throughput screening(HTS)for multitarget-directed ligands(MTDLs)using approved drugs,and fragment-based drug design has become a regular strategy to achieve an ideal multitarget combination.However,the unexpected presence of pan-assay interference compounds(PAINS)suspects in the development of MTDLs frequently results in nonspecific interactions or other undesirable effects leading to artefacts or false-positive data of biolog-ical assays.Publicly available filters can help to identify PAINS suspects;however,these filters cannot comprehensively conclude whether these suspects are“bad”or innocent.Additionally,these in silico ap-proaches may inappropriately label a ligand as PAINS.More than 80％of the initial hits can be identified as PAINS by the filters if appropriate biochemical tests are not used resulting in false positive data that are unacceptable for medicinal chemists in manuscript peer review and future studies.Therefore,extensive offline experiments should be used after online filtering to discriminate“bad”PAINS and avoid incorrect evaluation of good scaffolds.We suggest that the use of“Fair Trial Strategy”to identify interesting molecules in PAINS suspects to provide certain structure-function insight in MTDL development.