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Pharmacophore‐Based Drug Design and Biological Evaluation of Novel ABCB1 Inhibitors
Author(s) -
Zhang Shenglie,
Wei Yinxiang,
Li Qian,
Sun Haopeng,
Peng Hui,
You Qidong
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12081
Subject(s) - pharmacophore , multiple drug resistance , chemistry , pharmacology , drug , drug resistance , medicine , biology , stereochemistry , biochemistry , antibiotics , microbiology and biotechnology
Overexpression of ABCB1 is one of major barriers for multidrug resistance in chemotherapy and limits drug oral bioavailability. Inhibition of ABCB1 would sensitize multidrug resistance in clinical cancer chemotherapy. With this aim, a 3D pharmacophore model was created based on known ABCB1 inhibitors with correlation coefficient of 0.94, comprising three hydrophobic features and one hydrogen bond acceptor. It was further validated and used to search our in‐house 3D database for potential ABCB1 inhibitors. The inhibitory activities of the best hits were evaluated by several biological assays, such as rhodamine 123 accumulation assay, chemosensitization assay, multidrug resistance 1‐Madin‐Darby canine kidney cells/Madin‐Darby canine kidney cells permeability assay. Finally, compounds YZ‐3 and YZ‐16 were identified as potential leads to be developed in the designing of novel potent ABCB1 inhibitors.