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Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection

Fritzson, Ingela LU ; Svensson, Bo; Al-Karadaghi, Salam LU ; Walse, Björn; Wellmar, Ulf; Nilsson, Ulf LU ; da Graca Thrige, Dorthe and Jönsson, Stig (2010) In ChemMedChem 5(4). p.608-617
Abstract
A strategy that combines virtual screening and structureguided 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... (More)
A strategy that combines virtual screening and structureguided 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 IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Dihydroorotate dehydrogenase, drug discovery, fragment screening, inhibitors, structure-activity relationships
in
ChemMedChem
volume
5
issue
4
pages
608 - 617
publisher
Wiley-Blackwell
external identifiers
  • scopus:77950647749
ISSN
1860-7187
DOI
10.1002/cmdc.200900454
language
English
LU publication?
yes
id
a1336bb6-c6c5-4cc4-aff4-8bfd824a21bb (old id 1938648)
date added to LUP
2011-05-03 16:25:36
date last changed
2018-05-29 09:46:12
@article{a1336bb6-c6c5-4cc4-aff4-8bfd824a21bb,
  abstract     = {A strategy that combines virtual screening and structureguided 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 IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.},
  author       = {Fritzson, Ingela and Svensson, Bo and Al-Karadaghi, Salam and Walse, Björn and Wellmar, Ulf and Nilsson, Ulf and da Graca Thrige, Dorthe and Jönsson, Stig},
  issn         = {1860-7187},
  keyword      = {Dihydroorotate dehydrogenase,drug discovery,fragment screening,inhibitors,structure-activity relationships},
  language     = {eng},
  number       = {4},
  pages        = {608--617},
  publisher    = {Wiley-Blackwell},
  series       = {ChemMedChem},
  title        = {Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection},
  url          = {http://dx.doi.org/10.1002/cmdc.200900454},
  volume       = {5},
  year         = {2010},
}