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

• Published in: Archiv der Pharmazie (Weinheim) 2017-10, Vol.350 (10), p.n/a
• Main Authors: Macías Pérez, Martha E., Hernández Rodríguez, Maricarmen, Cabrera Pérez, Laura C., Fragoso‐Vázquez, M. Jonathan, Correa‐Basurto, José, Padilla‐Martínez, Itzia I., Méndez Luna, David, Mera Jiménez, Elvia, Flores Sandoval, César, Tamay Cach, Feliciano, Rosales‐Hernández, Martha C.
• Format: Article
• Language: English
• Subjects: Acetophenones - chemical synthesis; Acetophenones - chemistry; Acetophenones - pharmacology; Animals; Biphenyl Compounds - chemical synthesis; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Computer Simulation; Drug design; Humans; NADPH Oxidases - antagonists & inhibitors; Oxidative Stress - drug effects; Rats; Reactive oxygen species; Reactive Oxygen Species - metabolism; Structure-Activity Relationship; Superoxides - metabolism; Virtual screening
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201700041

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. Compound C8, one of the 18 designed compounds with chemical relationship to the NOX2 inhibitor diapocynin (C1), forms π–π interactions with the NOX2 subunit p47phox and exhibits antioxidant properties by inhibiting ROS production in endothelial cells. Targeting the aromatic region of p47phox through π‐interactions is important for inhibiting NOX activity.