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Inhibition of Human DHODH by 4‐Hydroxycoumarins, Fenamic Acids, and N ‐(Alkylcarbonyl)anthranilic Acids Identified by Structure‐Guided Fragment Selection
Author(s) -
Fritzson Ingela,
Svensson Bo,
AlKaradaghi Salam,
Walse Björn,
Wellmar Ulf,
Nilsson Ulf J.,
da Graça Thrige Dorthe,
Jönsson Stig
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900454
Subject(s) - anthranilic acid , chemistry , amino acid , biochemistry , stereochemistry
A strategy that combines virtual screening and structure‐guided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4‐hydroxycoumarins, fenamic acids, and N ‐(alkylcarbonyl)anthranilic acids. Structure‐guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N ‐(alkylcarbonyl)anthranilic acid class shows the most promising potency against human DHODH, with IC 50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.