2. Academic Validation
  3. Structure-activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport

Structure-activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport

  • Bioorg Med Chem. 2016 Jul 15;24(14):3184-91. doi: 10.1016/j.bmc.2016.05.039.
Ken-Ichi Miyata 1,  Yoshiaki Nakagawa 2,  Yasuhisa Kimura 2,  Kazumitsu Ueda 3,  Miki Akamatsu 4
Affiliations

Affiliations

  • 1 Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Otsuka Pharmaceutical Co., Ltd, Tokushima 771-0182, Japan. Electronic address: Miyata.Kenichi@otsuka.jp.
  • 2 Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
  • 3 Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan; Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8502, Japan.
  • 4 Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. Electronic address: akamatsu@kais.kyoto-u.ac.jp.
PMID: 27262425 DOI: 10.1016/j.bmc.2016.05.039
Abstract

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.

Keywords

Bidirectional transport assay; Dibenzoylhydrazines; Docking; P-glycoprotein; Structure–activity.

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