Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands

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 becom...

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Autores principales:	Jianbo Sun, Hui Zhong, Kun Wang, Na Li, Li Chen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Multitarget-directed ligands PAINS suspects In silico filtering Biochemical experiment Fair trial strategy Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/f560e80bb16a4f2e99ee310b9fb009cf
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spelling	oai:doaj.org-article:f560e80bb16a4f2e99ee310b9fb009cf2021-12-02T05:01:20ZGains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands2211-383510.1016/j.apsb.2021.02.023https://doaj.org/article/f560e80bb16a4f2e99ee310b9fb009cf2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S221138352100071Xhttps://doaj.org/toc/2211-3835Compounds 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 biological 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 approaches 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.Jianbo SunHui ZhongKun WangNa LiLi ChenElsevierarticleMultitarget-directed ligandsPAINS suspectsIn silico filteringBiochemical experimentFair trial strategyTherapeutics. PharmacologyRM1-950ENActa Pharmaceutica Sinica B, Vol 11, Iss 11, Pp 3417-3432 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Multitarget-directed ligands PAINS suspects In silico filtering Biochemical experiment Fair trial strategy Therapeutics. Pharmacology RM1-950
spellingShingle	Multitarget-directed ligands PAINS suspects In silico filtering Biochemical experiment Fair trial strategy Therapeutics. Pharmacology RM1-950 Jianbo Sun Hui Zhong Kun Wang Na Li Li Chen Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
description	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 biological 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 approaches 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.
format	article
author	Jianbo Sun Hui Zhong Kun Wang Na Li Li Chen
author_facet	Jianbo Sun Hui Zhong Kun Wang Na Li Li Chen
author_sort	Jianbo Sun
title	Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
title_short	Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
title_full	Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
title_fullStr	Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
title_full_unstemmed	Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands
title_sort	gains from no real pains: where ‘fair trial strategy’ stands in the development of multi-target ligands
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/f560e80bb16a4f2e99ee310b9fb009cf
work_keys_str_mv	AT jianbosun gainsfromnorealpainswherefairtrialstrategystandsinthedevelopmentofmultitargetligands AT huizhong gainsfromnorealpainswherefairtrialstrategystandsinthedevelopmentofmultitargetligands AT kunwang gainsfromnorealpainswherefairtrialstrategystandsinthedevelopmentofmultitargetligands AT nali gainsfromnorealpainswherefairtrialstrategystandsinthedevelopmentofmultitargetligands AT lichen gainsfromnorealpainswherefairtrialstrategystandsinthedevelopmentofmultitargetligands
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Gains from no real PAINS: Where ‘Fair Trial Strategy’ stands in the development of multi-target ligands

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