Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues

Martha E. Macías Pérez, Maricarmen Hernández Rodríguez, Laura C. Cabrera Pérez, M. Jonathan Fragoso-Vázquez, José Correa-Basurto, Itzia I. Padilla-Martínez, David Méndez Luna, Elvia Mera Jiménez, César Flores Sandoval, Feliciano Tamay Cach, Martha C. Rosales-Hernández

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Abstract

© 2017 Deutsche Pharmazeutische Gesellschaft Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O2•−). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2–C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π–π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity.
Original languageAmerican English
JournalArchiv der Pharmazie
DOIs
StatePublished - 1 Oct 2017

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