Structure-activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport.
We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation.
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Otsuka Pharmaceutical Co., Ltd, Tokushima 771-0182, Japan. Electronic address: Miyata.Kenichi@otsuka.jp.
Ken-Ichi
K
Miyata
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Yoshiaki
Y
Nakagawa
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
Yasuhisa
Y
Kimura
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8502, Japan.
Kazumitsu
K
Ueda
Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: akamatsu@kais.kyoto-u.ac.jp.
Miki
M
Akamatsu
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D006801:Humans; D006834:Hydrazines / Q000737:chemistry* / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D018374:LLC-PK1 Cells; D062105:Molecular Docking Simulation; D021281:Quantitative Structure-Activity Relationship; D011802:Quinidine / Q000378:metabolism*; D013552:Swine
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006834:Hydrazines; D011802:Quinidine
Bidirectional transport assay; Dibenzoylhydrazines; Docking; P-glycoprotein; Structure–activity