Dataset Information


Rational design of small molecule inhibitors targeting the Rac GTPase-p67(phox) signaling axis in inflammation.

ABSTRACT: 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.


PROVIDER: S-EPMC3292765 | BioStudies | 2012-01-01

REPOSITORIES: biostudies

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