title: Pharmacophore-based drug design and biological evaluation of novel ABCB1 inhibitors.
abstract: 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.
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Sheng-lie
authors.initials: SL
authors.lastname: Zhang
authors.forename: Yin-xiang
authors.initials: YX
authors.lastname: Wei
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Hao-peng
authors.initials: HP
authors.lastname: Sun
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Qi-dong
authors.initials: QD
authors.lastname: You
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000634:Aminoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D016208:Databases, Factual; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020014:K562 Cells; D061985:Madin Darby Canine Kidney Cells; D008956:Models, Chemical; D010539:Permeability / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D015363:Quinolones / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000634:Aminoquinolines; D052160:Benzothiazoles; D006575:Heterocyclic Compounds, 3-Ring; D015363:Quinolones; D020112:Rhodamine 123