TY - JOUR
T1 - Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues
AU - Macías Pérez, Martha E.
AU - Hernández Rodríguez, Maricarmen
AU - Cabrera Pérez, Laura C.
AU - Fragoso-Vázquez, M. Jonathan
AU - Correa-Basurto, José
AU - Padilla-Martínez, Itzia I.
AU - Méndez Luna, David
AU - Mera Jiménez, Elvia
AU - Flores Sandoval, César
AU - Tamay Cach, Feliciano
AU - Rosales-Hernández, Martha C.
N1 - Publisher Copyright:
© 2017 Deutsche Pharmazeutische Gesellschaft
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Drug design
KW - Reactive oxygen species
KW - Virtual screening
UR - http://www.scopus.com/inward/record.url?scp=85028411887&partnerID=8YFLogxK
U2 - 10.1002/ardp.201700041
DO - 10.1002/ardp.201700041
M3 - Artículo
C2 - 28833480
SN - 0365-6233
VL - 350
JO - Archiv der Pharmazie
JF - Archiv der Pharmazie
IS - 10
M1 - 1700041
ER -