Full Paper Aromatic Regions Govern the Recognition of NADPH Oxidase Inhibitors as Diapocynin and its Analogues Martha E. Mac  ıas P erez 1 , Maricarmen Hern andez Rodr  ıguez 1,2 , Laura C. Cabrera P erez 1 , M. Jonathan Fragoso-V azquez 3 , Jos e Correa-Basurto 1,2 , Itzia I. Padilla-Mart  ınez 4 , David M endez Luna 2 , Elvia Mera Jim enez 5 ,C esar Flores Sandoval 6 , Feliciano Tamay Cach 7 , and Martha C. Rosales-Hern andez 1 1 Laboratorio de Biof  ısica y Biocat alisis, Secci  on de Estudios de Posgrado e Investigaci  on de la Escuela Superior de Medicina del Instituto Polit ecnico Nacional, Ciudad de M exico, M exico 2 Laboratorio de Modelado Molecular y Dise~ no de F armacos, Secci  on de Estudios de Posgrado e Investigaci  on de la Escuela Superior de Medicina del Instituto Polit ecnico Nacional, Ciudad de M exico, M exico 3 Departamento de Qu  ımica Org anica, Escuela Nacional de Ciencias Biol  ogicas del Instituto Polit ecnico Nacional, Ciudad de M exico, M exico 4 Unidad Profesional Interdisciplinaria de Biotecnolog  ıa, Instituto Polit ecnico Nacional, Ciudad de M exico, M exico 5 Laboratorio de Cultivo Celular de la Secci  on de Estudios de Posgrado e Investigaci  on de la Escuela Superior de Medicina del Instituto Polit ecnico Nacional, Ciudad de M exico, M exico 6 Gerencia de Desarrollo de Materiales y Productos Qu  ımicos, Instituto Mexicano del Petr  oleo, Eje Central (L azaro C ardenas), Ciudad de M exico, M exico 7 Laboratorio de Investigaci  on de Bioqu  ımica, Secci  on de Estudios de Posgrado e Investigaci  on de la Escuela Superior de Medicina del Instituto Polit ecnico Nacional, Ciudad de M exico, M exico Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O 2 •À ). 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 p–p 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 p-interactions is important for inhibiting NOX activity. Keywords: Drug design / Reactive oxygen species / Virtual screening Received: February 15, 2017; Revised: July 20, 2017; Accepted: July 21, 2017 DOI 10.1002/ardp.201700041 : Additional supporting information may be found in the online version of this article at the publisher’s web-site. Introduction Oxidative stress plays a central role in the development of cardiovascular and microvascular complications in various Correspondence: Dr. Martha C. Rosales-Hern andez, Plan de San Luis y D  ıaz Mir  on s/n Casco de Santo Tom as, Delegaci  on Miguel Hidalgo, CP.11340, M exico, D.F., M exico. E-mail: marcrh2002@yahoo.com.mx Arch. Pharm. Chem. Life Sci. 2017, 350, e1700041 Archiv der Pharmazie ARCH RCH P HARM HARM ß 2017 Deutsche Pharmazeutische Gesellschaft www.archpharm.com (1 of 11) e1700041