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Integration of pharmacophore mapping and molecular docking in sequential virtual screening: towards the discovery of novel JAK2 inhibitors
Ist Teil von
RSC advances, 2017, Vol.7 (17), p.10353-10360
Ort / Verlag
Cambridge: Royal Society of Chemistry
Erscheinungsjahr
2017
Quelle
Free E-Journal (出版社公開部分のみ)
Beschreibungen/Notizen
An integrated virtual screening protocol by combining molecular docking and pharmacophore mapping was established to identify novel inhibitors of JAK2 from a commercial compound database. Twelve novel and structurally diverse hits were selected and subjected to
in vitro
biological tests, and three compounds (
A5
,
A6
and
A9
) with remarkable JAK2 inhibitory activity were identified. Then, the obtained structures were further used as the template for a subsequent similarity search, leading to the identification of another two promising compounds (
B2
and
B4
). Selectivity profiles of JAK subtype and
in vitro
anti-cancer activity of the promising compounds were studied, revealing the promising compound
B2
was of interest for further study because of its JAK2 selective profile, novelty of skeleton and significantly anti-proliferative effect against cancer cells. Finally, binding patterns of the compounds
A5
and
B2
were explored to provide a deeper insight for further structural optimization.