BioChem - DOS

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

Journal of chemical information and modeling

Gartan, Parveen; Khorsand, Fahimeh; Mizar, Pushpak; Vahokovski, Juha Ilmari; Cervantes, Luis F.; Haug, Bengt Erik; Brenk, Ruth; Brooks, Charles L.; Reuter, Nathalie

<P>Using a combination of multisite &lambda;&#x2212;dynamics (MS&lambda;D) 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 establishment of polypharmacologically targeting both enzymes and enhancing the potential for treatments addressing diseases like chronic obstructive pulmonary disease.</P><BR>[FIG OMISSION]</BR>

2024

American Chemical Society

1549-9596

1549-960x

64

3

pp.621-626

10.1021/acs.jcim.3c01949

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