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dc.creatorKováčiková, Lucia
dc.creatorGaikwad, Sunil
dc.creatorAlmášiová, Kristína
dc.creatorAlmássy, Ambroz
dc.creatorAddová, Gabriela
dc.creatorMájeková, Magdaléna
dc.creatorHanquet, Gilles
dc.creatorDobričić, Vladimir
dc.creatorBoháč, Andrej
dc.creatorŠtefek, Milan
dc.date.accessioned2024-02-27T14:56:35Z
dc.date.available2024-02-27T14:56:35Z
dc.date.issued2024
dc.identifier.issn1054-2523
dc.identifier.urihttps://farfar.pharmacy.bg.ac.rs/handle/123456789/5545
dc.description.abstractNovel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2)-substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 (N(2)-CH2CH2COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2)-substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C-terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors. (Figure presented.).
dc.publisherSpringer
dc.relationVEGA 2/0008/22
dc.relationVEGA 2/0103/22
dc.relationAPVV-20-0411
dc.relationAPVV-20-0543
dc.relationAPVV SK-SRB- 21-0047 (451-03-43/2022-09/02)
dc.relationAPVV SK-FR-22-0017
dc.relationThe Operation Program of Integrated Infrastructure for the project, Advancing University Capacity and Competence in Research, Development and Innovation (Accord), ITMS2014+: 313021×329 and ITMS2014+: 313021BUZ3 (Usccord) co-financedby the European Regional Development Fund.
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourceMedicinal Chemistry Research
dc.subjectAldehyde reductase
dc.subjectAldose reductase inhibitors
dc.subjectC-terminal loop
dc.subjectOxotriazinoindoles
dc.subjectSelectivity
dc.titleSelectivity of N(2)-substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase
dc.typearticle
dc.rights.licenseBY
dc.citation.volume33
dc.citation.spage492
dc.citation.epage503
dc.identifier.wos001161814000002
dc.identifier.doi10.1007/s00044-024-03194-3
dc.identifier.scopus2-s2.0-85185142904
dc.identifier.scopus001161814000002
dc.type.versionpublishedVersion


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