Virtual screening for novel openers of pancreatic K(ATP) channels.
Ligand-based virtual screening approaches were applied to search for new chemotype KCOs activating Kir6.2/SUR1 KATP channels. A total of 65 208 commercially available compounds, extracted from the ZINC archive, served as database for screening. In a first step, pharmacokinetic filtering via VolSurf reduced the initial database to 1913 compounds. Afterward, six molecules were selected as templates for similarity searches: similarity scores, obtained toward these templates, were calculated with the GRIND, FLAP, and TOPP approaches, which differently encode structural information into potential pharmacophores. In this way, we obtained 32 hit candidates, 16 via GRIND and eight each via FLAP and TOPP. For biological testing of the hit candidates, their effects on membrane potentials in HEK 293 cells expressing Kir6.2/SUR1 were studied. GRIND, FLAP, and TOPP all yielded hits, but no method top-ranked all the actives. Thus, parallel application of different approaches probably improves hit detection.
Carosati
Emanuele
E
Laboratory for Chemometrics and Cheminformatics, Chemistry Department, University of Perugia, Via Elce di Sotto, 10, I-06123 Perugia, Italy. emanuele@chemiome.chm.unipg.it
Mannhold
Raimund
R
Wahl
Philip
P
Hansen
John Bondo
JB
Fremming
Tinna
T
Zamora
Ismael
I
Cianchetta
Giovanni
G
Baroni
Massimo
M
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D016208:Databases, Factual; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D015640:Ion Channel Gating; D008564:Membrane Potentials / Q000187:drug effects; D008958:Models, Molecular; D015221:Potassium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D021281:Quantitative Structure-Activity Relationship; D011955:Receptors, Drug / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human