Related ArticlesPost-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR.
Bioorg Med Chem Lett. 2015 Aug 10;
Authors: Dahlin JL, Nissink JW, Francis S, Strasser JM, John K, Zhang Z, Walters MA
Abstract
Despite its wide use, not every high-throughput screen (HTS) yields chemical matter suitable for drug development campaigns, and seldom are 'go/no-go' decisions in drug discovery described in detail. This case report describes the follow-up of a 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one active from a cell-free HTS to identify small-molecule inhibitors of Rtt109-catalyzed histone acetylation. While this compound and structural analogs inhibited Rtt109-catalyzed histone acetylation in vitro, further work on this series was halted after several risk mitigation strategies were performed. Compounds with this chemotype had a poor structure-activity relationship, exhibited poor selectivity among other histone acetyltransferases, and tested positive in a ?-lactamase counter-screen for chemical aggregates. Furthermore, ALARM NMR demonstrated compounds with this chemotype grossly perturbed the conformation of the La protein. In retrospect, this chemotype was flagged as a 'frequent hitter' in an analysis of a large corporate screening deck, yet similar compounds have been published as screening actives or chemical probes versus unrelated biological targets. This report-including the decision-making process behind the 'no-go' decision-should be informative for groups engaged in post-HTS triage and highlight the importance of considering physicochemical properties in early drug discovery.
PMID: 26318992 [PubMed - as supplied by publisher]
[NMR paper] NMR Structural Mapping Reveals Promiscuous Interactions between Clathrin-Box Motif Sequences and the N-Terminal Domain of the Clathrin Heavy Chain.
NMR Structural Mapping Reveals Promiscuous Interactions between Clathrin-Box Motif Sequences and the N-Terminal Domain of the Clathrin Heavy Chain.
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Biochemistry. 2015 Apr 6;
Authors: Zhuo Y, Cano KE, Wang L, Ilangovan U, Hinck AP, Sousa R, Lafer EM
Abstract
Recruitment and organization of clathrin at endocytic sites to first form coated pits and then clathrin...
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[NMR paper] Identification and quantification of the doping agent GHRP-2 in seized unlabelled vials by NMR and MS: a case-report.
Identification and quantification of the doping agent GHRP-2 in seized unlabelled vials by NMR and MS: a case-report.
http://www.bionmr.com//www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--media.wiley.com-assets-2250-98-WileyOnlineLibrary-Button_120x27px_FullText.gif Related Articles Identification and quantification of the doping agent GHRP-2 in seized unlabelled vials by NMR and MS: a case-report.
Drug Test Anal. 2014 Mar;6(3):295-300
Authors: Gaudiano MC, Valvo L, Borioni A
PMID: 24446112
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11-11-2014 11:57 AM
[NMR paper] Micelle-bound conformations of neurohypophyseal hormone analogues modified with a C?-disubstituted residue: NMR and molecular modelling studies.
Micelle-bound conformations of neurohypophyseal hormone analogues modified with a C?-disubstituted residue: NMR and molecular modelling studies.
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J Biomol Struct Dyn. 2013;31(7):748-64
Authors: Sikorska E, Kwiatkowska A
Abstract
In this study, by applying a combined approach of NMR measurements and molecular modelling, the conformations and the interactions with membrane-like...
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11-07-2013 11:06 AM
Healthcare Stocks Alert: Taro Pharmaceutical Industries Ltd, EpiCept ... - SBWire (press release)
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Healthcare Stocks Alert: Taro Pharmaceutical Industries Ltd, EpiCept ...
SBWire (press release)
The Company's first diagnostic test, the nuclear magnetic resonance (NMR) LipoProfile test, directly measures the number of low density lipoprotein (LDL), particles in a blood sample and provides physicians and their patients with actionable ...
Healthcare Stocks Alert: Taro Pharmaceutical Industries Ltd, EpiCept ... - SBWire (press release)
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[Ryan's blog] What is Bosutinib? A Case for CASE
Source: Ryan's blog
What is Bosutinib? A Case for CASE
PKC Pharmaceuticals is working very hard to try and not only remedy the issues that have come out of the Bosutinib issue described in previous posts and in other media outlets, but to also really understand what went wrong, what...
Read more...
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06-07-2012 08:10 PM
[NMR paper] ALARM NMR: a rapid and robust experimental method to detect reactive false positives
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J Am Chem Soc. 2005 Jan 12;127(1):217-24
Authors: Huth JR, Mendoza R, Olejniczak ET, Johnson RW, Cothron DA, Liu Y, Lerner CG, Chen J, Hajduk PJ
High-throughput screening (HTS) of large compound collections typically results in numerous small molecule hits that must be carefully evaluated to identify valid drug...
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11-24-2010 11:14 PM
Synthesis, NMR characterization and divergent biological actions of 2'-hydroxy-cerami
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Bioorg Med Chem. 2010 Sep 17;
Authors: Szulc ZM, Bai A, Bielawski J, Mayroo N, Miller DE, Gracz H, Hannun YA, Bielawska A
A straightforward method for the...
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Post-doctoral Position in NMR and Structural Biology
Post-doctoral Position in NMR and Structural Biology
We are looking for a candidate to apply for a one-year post-doctoral position at University René Descartes, Paris, France. The project involves solution NMR and molecular modeling investigations of proteins and their complexes. The candidate must have a Ph.D. in physical chemistry or related field with experience in computational protein chemistry, structure-based drug design, protein modeling, and NMR spectroscopy. The candidate should be able to tackle the state-of-the-art methodologies necessary for protein modeling and...
Post-HTS case report and structural alert: Promiscuous 4-aroyl-1,5-disubstituted-3-hydroxy-2H-pyrrol-2-one actives verified by ALARM NMR.
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