Investigating Polypharmacology through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3.
Investigating Polypharmacology through Targeting Known Human Neutrophil Elastase Inhibitors to Proteinase 3.
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通过将已知的人类中性粒细胞弹性蛋白酶抑制剂靶向蛋白酶 3 来研究多药理学。
DOI：
10.1021/acs.jcim.3c01949
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发表时间：
2024
影响因子：
5.6
通讯作者：
Reuter,Nathalie
中科院分区：
文献类型：
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作者：
Gartan,Parveen;Khorsand,Fahimeh;Mizar,Pushpak;Vahokovski,JuhaIlmari;Cervantes,LuisF;Haug,BengtErik;Brenk,Ruth;Brooks3rd,CharlesL;Reuter,Nathalie
在体外IC50检测中结合使用多位点λ−动力学(MSλD)，我们评估了一种目前正在进行临床试验的支架的多药理潜力，该支架针对心肺疾病，抑制人中性粒细胞弹性蛋白酶(HNE)，有效抑制与中性粒细胞丝氨酸蛋白酶相关的蛋白3(PR3)。我们观察到的亲和力表明，二氢嘧啶酮支架可以作为一个合适的起点，以建立针对两种酶的多药物靶向，并增强治疗慢性阻塞性肺疾病等疾病的可能性。
Using a combination of multisite λ−dynamics (MSλD) together within vitroIC50assays, 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.