Investigating Polypharmacology through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3

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Abstract
Using a combination of multisite lambda-dynamics (MS lambda D) together with in vitro IC50 assays, we evaluated the polypharmacological potential of a scaffold currently in clinical trials for inhibition of human neutrophil elastase (HNE), targeting cardiopulmonary disease, for efficacious inhibition of Proteinase 3 (PR3), a related neutrophil serine proteinase. The affinities we observe suggest that the dihydropyrimidinone scaffold can serve as a suitable starting point for the establishment of polypharmacologically targeting both enzymes and enhancing the potential for treatments addressing diseases like chronic obstructive pulmonary disease.
Funding Information
  • Norges Forskningsr?d (245828, 294594, 245922)
  • National Institutes of Health (GM130587)
  • NRIS/Sigma2 (NN4700K)

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