Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches
Kelton L. B. dos Santos,
Jorddy N. Cruz,
Luciane B. Silva,
Ryan S. Ramos,
Moysés F. A. Neto,
Cleison C. Lobato,
Sirlene S. B. Ota,
Franco H. A. Leite,
Rosivaldo S. Borges,
Carlos H. T. P. da Silva,
Joaquín M. Campos,
Cleydson B. R. Santos
Affiliations
Kelton L. B. dos Santos
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Jorddy N. Cruz
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Luciane B. Silva
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Ryan S. Ramos
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Moysés F. A. Neto
Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana, 44036-900 Bahia, Brazil
Cleison C. Lobato
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Sirlene S. B. Ota
Nucleus of Studies and Selection of Bioactive Molecules, Institute of Health Sciences, Federal University of Pará, 66075-110 Belém-PA, Brazil
Franco H. A. Leite
Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana, 44036-900 Bahia, Brazil
Rosivaldo S. Borges
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Carlos H. T. P. da Silva
Computational Laboratory of Pharmaceutical Chemistry, University of São Paulo, 14040-903 Ribeirão Preto-SP, Brazil
Joaquín M. Campos
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary, Research ibs. Granada, University of Granada, 18071 Granada, Spain
Cleydson B. R. Santos
Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil
Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.
