Discovery of inhibitory fragments that selectively target Spire2−FMN2 interaction

2023
journal article
article
dc.abstract.enHere, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2–FMN2 but not the Spire1–FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H–15N HSQC nuclear magnetic resonance. Extensive structure–activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2–FMN2 interaction.pl
dc.affiliationWydział Chemii : Zakład Chemii Organicznejpl
dc.affiliationPion Prorektora ds. badań naukowych : Małopolskie Centrum Biotechnologiipl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Mikrobiologiipl
dc.affiliationSzkoła Doktorska Nauk Ścisłych i Przyrodniczychpl
dc.affiliationWydział Chemii : Zakład Krystalochemii i Krystalofizykipl
dc.contributor.authorKitel, Radosław - 227807 pl
dc.contributor.authorSurmiak, Ewa - 115465 pl
dc.contributor.authorBorggräfe, Janpl
dc.contributor.authorKalinowska-Tłuścik, Justyna - 128600 pl
dc.contributor.authorGolik, Przemysław - 114607 pl
dc.contributor.authorCzub, Mirosława - 167064 pl
dc.contributor.authorUzar, Wiktor - 386922 pl
dc.contributor.authorMusielak, Bogdan - 126144 pl
dc.contributor.authorMadej, Mariusz - 163594 pl
dc.contributor.authorPopowicz, Grzegorz M.pl
dc.contributor.authorDubin, Grzegorz - 127778 pl
dc.contributor.authorHolak, Tadeusz - 214380 pl
dc.date.accessioned2024-01-08T10:50:21Z
dc.date.available2024-01-08T10:50:21Z
dc.date.issued2023pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.additionalTadeusz Holak podpisany: Tad A. Holak. Bibliogr. s. 15727pl
dc.description.number23pl
dc.description.physical15715-15727pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume66pl
dc.identifier.doi10.1021/acs.jmedchem.3c00877pl
dc.identifier.eissn1520-4804pl
dc.identifier.issn0022-2623pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/325150
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeinne
dc.subtypeArticlepl
dc.titleDiscovery of inhibitory fragments that selectively target Spire2−FMN2 interactionpl
dc.title.journalJournal of Medicinal Chemistrypl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Here, we report the fragment-based drug discovery of potent and selective fragments that disrupt the Spire2–FMN2 but not the Spire1–FMN2 interaction. Hit fragments were identified in a differential scanning fluorimetry-based screen of an in-house library of 755 compounds and subsequently validated in multiple orthogonal biophysical assays, including fluorescence polarization, microscale thermophoresis, and 1H–15N HSQC nuclear magnetic resonance. Extensive structure–activity relationships combined with molecular docking followed by chemical optimization led to the discovery of compound 13, which exhibits micromolar potency and high ligand efficiency (LE = 0.38). Therefore, this fragment represents a validated starting point for the future development of selective chemical probes targeting the Spire2–FMN2 interaction.
dc.affiliationpl
Wydział Chemii : Zakład Chemii Organicznej
dc.affiliationpl
Pion Prorektora ds. badań naukowych : Małopolskie Centrum Biotechnologii
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Mikrobiologii
dc.affiliationpl
Szkoła Doktorska Nauk Ścisłych i Przyrodniczych
dc.affiliationpl
Wydział Chemii : Zakład Krystalochemii i Krystalofizyki
dc.contributor.authorpl
Kitel, Radosław - 227807
dc.contributor.authorpl
Surmiak, Ewa - 115465
dc.contributor.authorpl
Borggräfe, Jan
dc.contributor.authorpl
Kalinowska-Tłuścik, Justyna - 128600
dc.contributor.authorpl
Golik, Przemysław - 114607
dc.contributor.authorpl
Czub, Mirosława - 167064
dc.contributor.authorpl
Uzar, Wiktor - 386922
dc.contributor.authorpl
Musielak, Bogdan - 126144
dc.contributor.authorpl
Madej, Mariusz - 163594
dc.contributor.authorpl
Popowicz, Grzegorz M.
dc.contributor.authorpl
Dubin, Grzegorz - 127778
dc.contributor.authorpl
Holak, Tadeusz - 214380
dc.date.accessioned
2024-01-08T10:50:21Z
dc.date.available
2024-01-08T10:50:21Z
dc.date.issuedpl
2023
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.additionalpl
Tadeusz Holak podpisany: Tad A. Holak. Bibliogr. s. 15727
dc.description.numberpl
23
dc.description.physicalpl
15715-15727
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
66
dc.identifier.doipl
10.1021/acs.jmedchem.3c00877
dc.identifier.eissnpl
1520-4804
dc.identifier.issnpl
0022-2623
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/325150
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
inne
dc.subtypepl
Article
dc.titlepl
Discovery of inhibitory fragments that selectively target Spire2−FMN2 interaction
dc.title.journalpl
Journal of Medicinal Chemistry
dc.typepl
JournalArticle
dspace.entity.type
Publication

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