Cramer Joerg, Kopp Stephan, Bates Susan E, Chiba Peter, Ecker Gerhard F
BioChemInformatics, Intervet Innovation GmbH, Zur Probstei, 55270 Schwabenheim, Germany.
ChemMedChem. 2007 Dec;2(12):1783-8. doi: 10.1002/cmdc.200700160.
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.
多药耐药转运蛋白P-糖蛋白/ABCB1和ABCG2通过能量依赖的外排作用限制了大量细胞生长抑制剂和细胞毒性药物的作用。在实验模型中，泵抑制剂可恢复对这些药物的敏感性。这两种转运蛋白均表现出非常广泛且部分重叠的底物特异性。普罗帕酮类似物是包括P-糖蛋白、ABCG2以及微生物泵在内的大量药物外排泵的抑制剂。在此，针对这一类化合物与两种人类ABC转运蛋白ABCB1和ABCG2的相互作用进行了研究。数据表明，在同一化学骨架内，选择性指数跨越三个数量级。具有最高选择性指数的化合物含有一个不可电离的氮原子。定性和定量药效团模型表明，疏水性、可旋转键的数量以及氢键受体的数量是活性和选择性的关键特征。
