In silico identification and in vitro validation of potential cholestatic compounds through 3D ligand-based pharmacophore modeling of BSEP inhibitors.
Drug-induced cholestasis is a frequently observed side effect of drugs and is often caused by an unexpected interaction with the bile salt export pump (BSEP/ABCB11). BSEP is the key membrane transporter responsible for the transport of bile acids from hepatocytes into bile. Here, we developed a pharmacophore model that describes the molecular features of compounds associated with BSEP inhibitory activity. To generate input and validation data sets, in vitro experiments with membrane vesicles overexpressing human BSEP were used to assess the effect of compounds (50 μM) on BSEP-mediated (3)H-taurocholic acid transport. The model contains two hydrogen bond acceptor/anionic features, two hydrogen bond acceptor vector features, four hydrophobic/aromatic features, and exclusion volumes. The pharmacophore was validated against a set of 59 compounds, including registered drugs. The model recognized 9 out of 12 inhibitors (75%), which could not be identified based on general parameters, such as molecular weight or SlogP, alone. Finally, the model was used to screen a virtual compound database. A number of compounds found via virtual screening were tested and displayed statistically significant BSEP inhibition, ranging from 13 ± 1% to 67 ± 7% of control (P < 0.05). In conclusion, we developed and validated a pharmacophore model that describes molecular features found in BSEP inhibitors. The model may be used as an in silico screening tool to identify potentially harmful drug candidates at an early stage in drug development.
Computational Discovery and Design (CDD) Group, Centre for Molecular and Biomolecular Informatics (CMBI), Radboud university medical center , P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
Tina
T
Ritschel
Susanne M A
SM
Hermans
Marieke
M
Schreurs
Jeroen J M W
JJ
van den Heuvel
Jan B
JB
Koenderink
Rick
R
Greupink
Frans G M
FG
Russel
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D003198:Computer Simulation; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D013656:Taurocholic Acid / Q000378:metabolism
C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D008024:Ligands; D013656:Taurocholic Acid