Predicting ligand interactions with ABC transporters in ADME.
ABC-type drug efflux pumps, e.g., ABCB1 (=P-glycoprotein, =MDR1), ABCC1 (=MRP1), and ABCG2 (=MXR, =BCRP), confer a multi-drug resistance (MDR) phenotype to cancer cells. Furthermore, the important contribution of ABC transporters for bioavailability, distribution, elimination, and blood-brain barrier permeation of drug candidates is increasingly recognized. This review presents an overview on the different computational methods and models pursued to predict ABC transporter substrate properties of drug-like compounds. They encompass ligand-based approaches ranging from 'simple rule'-based efforts to sophisticated machine learning methods. Many of these models show excellent performance for the data sets used. However, due to the complex nature of the applied methods, useful interpretation of the models that can be directly translated into chemical structures by the medicinal chemist is rather difficult. Additionally, very recent and promising attempts in the field of structure-based modeling of ABC transporters, which embody homology modeling as well as recently published X-ray structures of murine ABCB1, will be discussed.
Demel
Michael A
MA
University of Vienna, Department of Medicinal Chemistry, Emerging Field Pharmacoinformatics, Althanstrasse 14, AT-1090 Vienna.
Krämer
O
O
Ettmayer
Peter
P
Haaksma
Eric E J
EE
Ecker
Gerhard F
GF
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000042:Absorption; D000818:Animals; D003198:Computer Simulation; D064420:Drug-Related Side Effects and Adverse Reactions; D005544:Forecasting; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D018528:ATP-Binding Cassette Transporters; D008024:Ligands; D004364:Pharmaceutical Preparations