J Chem Inf Model - Computational repositioning and experimental validation of approved drugs for HIF-prolyl hydroxylase inhibition.

Tópicos

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Resumo

HIF stability and activation are governed by a family of dioxygenases called HIF prolyl-4-hydroxylases (PHDs). It has been identified as a new target to augment the adaptive machinery that governs cytoprotection in disorders associated with ischemia/reperfusion, inflammation, and oxidative stress. In this sense, PHD inhibition has been proposed to mimic, at least in part, the protective effects of exposure to hypoxia. Exploiting drug polypharmacology to identify novel modes of actions for drug repurposing has gained significant attention in the current era of weak drug pipelines. The present work plan aims at giving new purpose to some well-established FDA-approved drugs. Here, we propose that by combining the literature survey, docking, and manual interpretation altogether, we were able to perform virtual screening on FDA-approved drugs to identify potential PHD inhibitors. Upon screening of 1537 marketed drugs, a final set of six hits were selected for experimental testing. All six drugs were divers, and immuno blotting was carried out to evaluate their ability to upregulate HIF in order to validate our hypothesis. Out of the six, three drugs showed significant upregulation of HIF possibly by inhibiting the PHD. It is believed that the appropriate use of the literature survey, docking, manual interpretation, and experimental validation strategy in the drug design process should improve the ability to identify hits and confirm their potential to serve as basis for drug repurposing.

Resumo Limpo

hif stabil activ govern famili dioxygenas call hif prolylhydroxylas phds identifi new target augment adapt machineri govern cytoprotect disord associ ischemiareperfus inflamm oxid stress sens phd inhibit propos mimic least part protect effect exposur hypoxia exploit drug polypharmacolog identifi novel mode action drug repurpos gain signific attent current era weak drug pipelin present work plan aim give new purpos wellestablish fdaapprov drug propos combin literatur survey dock manual interpret altogeth abl perform virtual screen fdaapprov drug identifi potenti phd inhibitor upon screen market drug final set six hit select experiment test six drug diver immuno blot carri evalu abil upregul hif order valid hypothesi six three drug show signific upregul hif possibl inhibit phd believ appropri use literatur survey dock manual interpret experiment valid strategi drug design process improv abil identifi hit confirm potenti serv basi drug repurpos

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