Identification of Novel Protein Kinase Receptor Type 2 Inhibitors Using Pharmacophore and Structure-Based Virtual Screening
Josiane V. Cruz,
Moysés F. A. Neto,
Luciane B. Silva,
Ryan da S. Ramos,
Josivan da S. Costa,
Davi S. B. Brasil,
Cleison C. Lobato,
Glauber V. da Costa,
José Adolfo H. M. Bittencourt,
Carlos H. T. P. da Silva,
Franco H. A. Leite,
Cleydson B. R. Santos
Affiliations
Josiane V. Cruz
Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Moysés F. A. Neto
Laboratory Molecular Modeling, Estadual University of Feira de Santana, Bahia 44036-900, Brazil
Luciane B. Silva
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Ryan da S. Ramos
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Josivan da S. Costa
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Davi S. B. Brasil
Institute of Technology, Federal University of Pará, Pará, Amazon, Belém 66075-900, Brazil
Cleison C. Lobato
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Glauber V. da Costa
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
José Adolfo H. M. Bittencourt
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
Carlos H. T. P. da Silva
Laboratory of Computational Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14040-020, Brazil
Franco H. A. Leite
Laboratory Molecular Modeling, Estadual University of Feira de Santana, Bahia 44036-900, Brazil
Cleydson B. R. Santos
Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
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.
