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Fakulteta za farmacijo, Ljubljana (FFALJ)
  • Galectin-8N-selective 4-halophenylphthalazinone-galactals double π stack in a unique pocket
    van Klaveren, Sjors ...
    Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological ... purposes. Structure-guided design led to the discovery of potent and selective glycomimetic–heterocycle hybrid ligands, with a 4-(p-bromophenyl)phthalazinone derivative displaying a 34 μM Kd for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 Å resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and in vitro ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.
    Vir: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 15, iss. 8, 2024, str. 1319-1324)
    Vrsta gradiva - članek, sestavni del ; neleposlovje za odrasle
    Leto - 2024
    Jezik - angleški
    COBISS.SI-ID - 203686403

    Povezava(-e):

    https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00212
    DOI

vir: ACS Medicinal Chemistry Letters. - ISSN 1948-5875 (Vol. 15, iss. 8, 2024, str. 1319-1324)

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