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Molecules ; 23(2)2018 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-29463017


The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The compounds were analyzed to ponatinib and WEHI-345, which also used as a control. At least one of the compounds exhibited suitable pharmacokinetic properties, low toxicity and an interesting binding affinity and high fitness compared with the crystallographic pose of WEHI-345 in complex with RIPK2. This compound also possessed suitable synthetic accessibility, rendering it a potential and very promising RIPK2 inhibitor to be further investigated in regards to different diseases, particularly inflammatory ones.

Imidazóis/química , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Piridazinas/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Cristalografia por Raios X , Humanos , Imidazóis/uso terapêutico , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Transdução de Sinais/efeitos dos fármacos , Interface Usuário-Computador