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

Abstract

Bardoxolone methyl (CDDO-Me), a synthetic derivative of the naturally occurring triterpenoid oleanolic acid, displays strong antioxidant, anticancer and anti-infammatory activities, according to diferent bibliographical sources. However, the understanding of its molecular mechanism is missing. Furthermore, CDDO-Me has displayed a signifcant cytotoxicity against various types of cancer cells. CDDO-Me has a noticeable hydrophobic character and several of its efects could be attributed to its ability to be incorporated inside the biological membrane and therefore modify its structure and specifcally 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 specifcally orients so that the cyano group lean towards the phospholipid interface and it specifcally interacts with particular phospholipids. Signifcantly, in the membrane the CDDO-Me molecules specifcally 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.