Identificação de novos inibidores do Receptor de Interação de Proteína Tirosina Quinase 2 com potencial atividade anti-inflamatória através do ensino da química medicinal

Abstract

Introduction: The Receptor Interacting tyrosine Kinase 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases, which signals downstream of intracellular sensors nucleotide-binding oligomerization domain 1 and 2 (NOD1 and NOD2) to promote a productive inflammatory response. However, excessive NOD2 signaling has been associated with several diseases, including sarcoidosis disease and rheumatoid arthritis, so that the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of proinflammatory secretion activity. Objective: Thus, the purpose of this study was to plan new inhibitors of RIPK2 with potential anti-inflammatory activity in rheumatoid arthritis. Methodology: A pharmacophoric model was constructed based on the crystallographic pose of Ponatinib, a potent inhibitor of RIPK2 and another 30 inhibitors selected from the BindingDB database. The selection of the compounds was performed from the ZINC database through available compounds, followed by pharmacokinetic, toxicological and biological activity predictions potential of the selected compounds. Then, the molecular coupling was performed to identify the likely interactions as well as binding affinity for RIPK2. Thereafter, the molecular overlap of the compounds selected herein and were analyzed for Ponatinib and WEHI-345, also used as a control. And therefore, the viability of the compound to be synthesized was determined. Results and discussion: After calculations, the compound ZINC91881108 showed a pharmacokinetic and toxicological analysis in silica within the established parameters and good binding affinity when compared to the crystallographic pose of WEHI-345 in complex with RIPK2. Conclusions: This compound also has moderate synthetic accessibility, resulting in a potential and promising inhibitor of RIPK2 to be investigated with interest in different diseases, in particular the inflammatory