Rational design of small molecule inhibitors targeting the Rac GTPase - p67phox signaling axis in inflammation
| Autor: | Jacek Biesiada, Jarek Meller, William L. Seibel, Yi Zheng, Sachin Kumar, Kathleen Szczur, Ariel Mizrahi, Marie-Dominique Filippi, Filippo Marchioni, Mirosław Kordos, Edgar Pick, Emily E. Bosco |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Enzyme complex
Neutrophils Clinical Biochemistry RAC1 HL-60 Cells Biochemistry Article 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Drug Discovery Humans Computer Simulation Molecular Biology 030304 developmental biology Pharmacology Inflammation 0303 health sciences NADPH oxidase Binding Sites biology Superoxide Rational design General Medicine Phosphoproteins Small molecule 3. Good health Protein Structure Tertiary Benzoxazines rac GTP-Binding Proteins Rac GTP-Binding Proteins chemistry 030220 oncology & carcinogenesis Drug Design biology.protein Molecular Medicine Pyrazoles Signal transduction Reactive Oxygen Species Signal Transduction |
| Popis: | Summary The NADPH oxidase enzyme complex, NOX2, is responsible for reactive oxygen species production in neutrophils and has been recognized as a key mediator of inflammation. Here, we have performed rational design and in silico screen to identify a small molecule inhibitor, Phox-I1, targeting the interactive site of p67 phox with Rac GTPase, which is a necessary step of the signaling leading to NOX2 activation. Phox-I1 binds to p67 phox with a submicromolar affinity and abrogates Rac1 binding and is effective in inhibiting NOX2-mediated superoxide production dose-dependently in human and murine neutrophils without detectable toxicity. Medicinal chemistry characterizations have yielded promising analogs and initial information of the structure-activity relationship of Phox-I1. Our studies suggest the potential utility of Phox-I class inhibitors in NOX2 oxidase inhibition and present an application of rational targeting of a small GTPase-effector interface. |
| Databáze: | OpenAIRE |
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