The Ecstasy and Agony of Assay Interference Compounds

Aldrich, Courtney C.; Bertozzi, Carolyn R.; Georg, Gunda I.; Kiessling, Laura L.; Lindsley, Craig W.; Liotta, Dennis; Merz, Kenneth M.; Schepartz, Alanna; Wang, Shaomeng

doi:10.1021/acs.jcim.7b00105

Cited by 49 publications

(72 citation statements)

References 40 publications

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“… 13 , 16 , 17 Hence, differentiating between multitarget activity and assay interference has become a major task in biological screening and medicinal chemistry. 17 In addition to their drug discovery relevance, small molecules with true multitarget activity are also of high interest for basic research in order to explore why and how such chemical entities are capable of forming specific interactions with multiple targets, especially if these targets are only distantly related or unrelated and have different functions.…”

Section: Introductionmentioning

confidence: 99%

X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design

2018

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Compounds with multitarget activity (promiscuity) are increasingly sought in drug discovery. However, promiscuous compounds are often viewed controversially in light of potential assay artifacts that may give rise to false-positive activity annotations. We have reasoned that the strongest evidence for true multitarget activity of small molecules would be provided by experimentally determined structures of ligand–target complexes. Therefore, we have carried out a systematic search of currently available X-ray structures for compounds forming complexes with different targets. Rather unexpectedly, 1418 such crystallographic ligands were identified, including 702 that formed complexes with targets from different protein families (multifamily ligands). About half of these multifamily ligands originated from the medicinal chemistry literature, making it possible to consider additional target annotations and search for analogues. From 168 distinct series of analogues containing one or more multifamily ligands, 133 unique analogue-series-based scaffolds were isolated that can serve as templates for the design of new compounds with multitarget activity. As a part of our study, all of the multifamily ligands we have identified and the analogue-series-based scaffolds are made freely available.

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Section: Introductionmentioning

confidence: 99%

X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design

2018

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“…When screening for target inhibitor drugs, it is essential to reliably identify pan-assay interference compounds (PAINS) ( 90 ) that might show up as false positives. For this purpose, the drug panel was tested in SPRINT reactions that constitutively transcribe a Cas13a target without regulatory components such as riboswitches or aTFs.…”

Section: Resultsmentioning

confidence: 99%

SPRINT: a Cas13a-based platform for detection of small molecules

Iwasaki

Batey

2020

Nucleic Acids Research

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Recent efforts in biological engineering have made detection of nucleic acids in samples more rapid, inexpensive and sensitive using CRISPR-based approaches. We expand one of these Cas13a-based methods to detect small molecules in a one-batch assay. Using SHERLOCK-based profiling of in vitrotranscription (SPRINT), in vitro transcribed RNA sequence-specifically triggers the RNase activity of Cas13a. This event activates its non-specific RNase activity, which enables cleavage of an RNA oligonucleotide labeled with a quencher/fluorophore pair and thereby de-quenches the fluorophore. This fluorogenic output can be measured to assess transcriptional output. The use of riboswitches or proteins to regulate transcription via specific effector molecules is leveraged as a coupled assay that transforms effector concentration into fluorescence intensity. In this way, we quantified eight different compounds, including cofactors, nucleotides, metabolites of amino acids, tetracycline and monatomic ions in samples. In this manner, hundreds of reactions can be easily quantified in a few hours. This increased throughput also enables detailed characterization of transcriptional regulators, synthetic compounds that inhibit transcription, or other coupled enzymatic reactions. These SPRINT reactions are easily adaptable to portable formats and could therefore be used for the detection of analytes in the field or at point-of-care situations.

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“…First, using substructural pattern matchers implemented in ZINC15, 23 the 14 experimentally confirmed hits were found to be free of chemical aggregation liabilities. 24 Furthermore, we followed a recent ACS editorial 25 and this journal requirements (http://pubs.acs.org/paragonplus/submission/jmcmar/jmcmar_authguide.pdf) for the evaluation of pan-assay interference compounds (PAINS) 26 . Although several recent studies, 27,28,29 demonstrated that PAINS alerts are not reliable indicators of assay interference propensity, we have performed this analysis and found that none of the hits possessed any PAINS alerts.…”

Section: Resultsmentioning

confidence: 99%

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

et al. 2018

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The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.

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The Ecstasy and Agony of Assay Interference Compounds

Cited by 49 publications

References 40 publications

X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design

X-ray-Structure-Based Identification of Compounds with Activity against Targets from Different Families and Generation of Templates for Multitarget Ligand Design

SPRINT: a Cas13a-based platform for detection of small molecules

Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors

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