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Multispecificity of Drug Transporters: Probing Inhibitor Selectivity for the Human Drug Efflux Transporters ABCB1 and ABCG2
Author(s) -
Cramer Joerg,
Kopp Stephan,
Bates Susan E.,
Chiba Peter,
Ecker Gerhard F.
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700160
Subject(s) - efflux , transporter , chemistry , p glycoprotein , abcg2 , drug , selectivity , pharmacophore , multiple drug resistance , stereochemistry , atp binding cassette transporter , pharmacology , biochemistry , combinatorial chemistry , biology , antibiotics , gene , catalysis
Multidrug resistance transporters P‐glycoprotein/ABCB1 and ABCG2 limit the effect of a large number of cytostatic and cytotoxic drugs by energy‐dependent efflux. In experimental models, pump inhibitors reestablish sensitivity towards these drugs. Both transporters demonstrate remarkably broad and partly overlapping substrate specificity. Propafenone analogues are inhibitors of a large number of drug efflux pumps including P‐glycoprotein and ABCG2 as well as the microbial pumps. Here the two human ABC transporters ABCB1 and ABCG2 have been studied with respect to interaction with this class of compounds. Data indicate that within the same chemical scaffold, selectivity indices span three orders of magnitude. Compounds with the highest selectivity indices contain a non‐ionizable nitrogen atom. Qualitative and quantitative pharmacophore models indicate that hydrophobicity, the number of rotatable bonds, and the number of H‐bond acceptors are key features for both activity and selectivity.