Investigating Polypharmacology through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3.
Parveen GartanFahimeh KhorsandPushpak MizarJuha Ilmari VahokovskiLuis F CervantesBengt Erik HaugRuth BrenkCharles L Brooks IiiNathalie ReuterPublished in: Journal of chemical information and modeling (2024)
Using a combination of multisite λ-dynamics (MSλD) together with in vitro IC 50 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.
Keyphrases
- endothelial cells
- chronic obstructive pulmonary disease
- clinical trial
- cancer therapy
- induced pluripotent stem cells
- mass spectrometry
- multiple sclerosis
- pluripotent stem cells
- ms ms
- randomized controlled trial
- tissue engineering
- drug delivery
- human health
- risk assessment
- cystic fibrosis
- protein kinase
- double blind