Breast cancer resistance protein (BCRP/ABCG2): New inhibitors and QSAR studies by a 3D linear solvation energy approach

• Published in: European journal of pharmaceutical sciences 2009-08, Vol.38 (1), p.39-46
• Main Authors: Nicolle, Edwige, Boccard, Julien, Guilet, David, Dijoux-Franca, Marie-Geneviève, Zelefac, Fabien, Macalou, Sira, Grosselin, Jeanne, Schmidt, Julien, Carrupt, Pierre-Alain, Di Pietro, Attilio, Boumendjel, Ahcène
• Format: Article
• Language: English
• Subjects: 3D-QSAR; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - chemistry; ATP-Binding Cassette Transporters - genetics; Bacteriology; BCRP; Biochemistry, Molecular Biology; Biodiversity and Ecology; Biological and medical sciences; Biological Transport - drug effects; Cell Line; Environmental Sciences; Flavonoids; Flavonoids - chemistry; Flavonoids - pharmacology; General pharmacology; Genomics; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Least-Squares Analysis; Life Sciences; Medical sciences; Microbiology and Parasitology; Mitoxantrone - metabolism; Models, Molecular; Molecular Conformation; Molecular Structure; Morus - chemistry; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - chemistry; Neoplasm Proteins - genetics; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Plant Bark - chemistry; Principal Component Analysis; Quantitative Structure-Activity Relationship; Reproducibility of Results; Surface Properties; Transfection; VolSurf descriptors
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2009.05.012

A series of compounds derived from naturally occurring flavonoids and synthetic analogs have been evaluated on cell lines overexpressing the wild-type breast cancer resistance protein (BCRP/ABCG2) half-transporter. Human ABCG2-transfected cells were used for screening their inhibitory activity. Five new natural compounds obtained from Morus mesozygia Stapf and one synthetic chromone, comprising a flavonoidic scaffold, were also evaluated. Based on the results obtained with a total of 34 compounds, a 3D linear solvation energy QSAR was investigated by VolSurf descriptors of molecular-interaction fields (MIFs) related to hydrophobic-interaction forces, polarisability and hydrogen-bonding capacity. Accuracy of the constructed 3D-QSAR model was attested by a correlation coefficient r 2 of 0.77. Shape parameters and hydrophobicity were revealed to be major physicochemical parameters responsible for the inhibition activity of flavonoid derivatives and synthetic analogs towards ABCG2, whereas hydrogen-bond donor capacity appeared highly unfavorable.