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

Using a combination of multisite λ−dynamics
(MSλD)
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.