title: In silico prediction of substrate properties for ABC-multidrug transporters.
abstract: Overexpression of ABC (ATP-binding cassette)-type drug efflux pumps, such as ABCB1, ABCC1 and ABCG2 in cancer cells confers multi-drug resistance (MDR) and represents a major cause of treatment failures in cancer therapy. Furthermore, there is increasing evidence for the important contribution of ABC-transporters to bioavailability, distribution, elimination and blood-brain barrier permeation of drug candidates. This review presents an overview on the different computational methods and models pursued to predict ABC-transporter substrate properties of drug-like compounds. They range from linear discriminant analysis to pharmacophore modelling and machine learning algorithms. Many of these models show a satisfying performance within the study-specific, defined chemical space but general applicability for the whole drug-like chemical space still needs to be proven. First attempts aiming towards selectivity profiling for ligands of the two polyspecific transporters ABCB1 and ABCG2 is also discussed. This might pave the way for a pharmacological profiling of compound series with special focus on their ADMET (absorption, distribution, metabolism, excretion and toxicity) properties.
authors: Department of Medicinal Chemistry, University of Vienna, Emerging Field Pharmacoinformatics, Wien, Althanstrasse 14, Austria.
authors: Michael A
authors: MA
authors: Demel
authors: R
authors: R
authors: Schwaha
authors: O
authors: O
authors: Krämer
authors: P
authors: P
authors: Ettmayer
authors: Eric Ej
authors: EE
authors: Haaksma
authors: Gerhard F
authors: GF
authors: Ecker
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000465:Algorithms; D003198:Computer Simulation; D005544:Forecasting; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D008024:Ligands; D009363:Neoplasm Proteins; D004364:Pharmaceutical Preparations