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

ABSTRACT: 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.

SUBMITTER: Gartan P

PROVIDER: S-EPMC10865350 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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

Gartan Parveen P Khorsand Fahimeh F Mizar Pushpak P Vahokovski Juha Ilmari JI Cervantes Luis F LF Haug Bengt Erik BE Brenk Ruth R Brooks Charles L CL Reuter Nathalie N

Journal of chemical information and modeling 20240126 3

Using a combination of multisite λ-dynamics (MSλD) together with <i>in vitro</i> IC<sub>50</sub> 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 establishm ...[more]

PMID: 38276895

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