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Location, Orientation and Aggregation of Bardoxolone-ME, CDDO-ME, in a Complex Phospholipid Bilayer Membrane

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Abstract

Bardoxolone methyl (CDDO-Me), a synthetic derivative of the naturally occurring triterpenoid oleanolic acid, displays strong antioxidant, anticancer and anti-inflammatory activities, according to different bibliographical sources. However, the understanding of its molecular mechanism is missing. Furthermore, CDDO-Me has displayed a significant cytotoxicity against various types of cancer cells. CDDO-Me has a noticeable hydrophobic character and several of its effects could be attributed to its ability to be incorporated inside the biological membrane and therefore modify its structure and specifically interact with its components. In this study, we have used full-atom molecular dynamics to determine the location, orientation and interactions of CDDO-Me in phospholipid model membranes. Our results support the location of CDDO-Me in the middle of the membrane, it specifically orients so that the cyano group lean towards the phospholipid interface and it specifically interacts with particular phospholipids. Significantly, in the membrane the CDDO-Me molecules specifically interact with POPE and POPS. Moreover, CDDO-Me does not aggregates in the membrane but it forms a complex conglomerate in solution. The formation of a complex aggregate in solution might hamper its biological activity and therefore it should be taken into account when intended to be used in clinical assays. This work should aid in the development of these molecules opening new avenues for future therapeutic developments.

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Acknowledgements

We would like to thank Prof. T. Giorgino for his invaluable help using the VMD Diffusion Coefficient plugin. NAMD was developed by the Theoretical and Computational Biophysics Group in the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champain. We are very grateful to SIATDI, Universidad Miguel Hernández (UMH) for the generous use of the UMH Computer Cluster. This work was not funded by any external or internal funding agencies.

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Authors and Affiliations

  1. Physics and Computer Architecture Department, Desarrollo e Innovación en Biotecnología Sanitaria (IDiBE), Universitas “Miguel Hernández”, 03202, Elche-Alicante, Spain

    Vicente Galiano

  2. Instituto de Biología Molecular y Celular (IBMC), Desarrollo e Innovación en Biotecnología Sanitaria (IDiBE), Universitas “Miguel Hernández”, 03202, Elche-Alicante, Spain

    José A. Encinar & José Villalaín

  3. Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria (IDiBE), Universitas “Miguel Hernández”, 03202, Elche-Alicante, Spain

    José A. Encinar & José Villalaín

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  1. Vicente Galiano
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Correspondence to José Villalaín.

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Galiano, V., Encinar, J.A. & Villalaín, J. Location, Orientation and Aggregation of Bardoxolone-ME, CDDO-ME, in a Complex Phospholipid Bilayer Membrane. J Membrane Biol 253, 115–128 (2020). https://doi.org/10.1007/s00232-020-00106-5

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