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

doi:10.3390/molecules25051245

Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Molecules. 2020 Mar 10;25(5):1245. doi: 10.3390/molecules25051245.

Authors

Kelton L B Dos Santos^{1

2}, Jorddy N Cruz¹, Luciane B Silva¹, Ryan S Ramos¹, Moysés F A Neto³, Cleison C Lobato^{1

2}, Sirlene S B Ota², Franco H A Leite³, Rosivaldo S Borges^{1

2}, Carlos H T P da Silva^{4

5}, Joaquín M Campos⁶, Cleydson B R Santos^{1

2}

Affiliations

¹ Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, 68902-280 Macapá-AP, Brazil.
² Nucleus of Studies and Selection of Bioactive Molecules, Institute of Health Sciences, Federal University of Pará, 66075-110 Belém-PA, Brazil.
³ Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana, 44036-900 Bahia, Brazil.
⁴ Computational Laboratory of Pharmaceutical Chemistry, University of São Paulo, 14040-903 Ribeirão Preto-SP, Brazil.
⁵ Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, 14090-901 Ribeirão Preto-SP, Brazil.
⁶ Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary, Research ibs. Granada, University of Granada, 18071 Granada, Spain.

Abstract

Adenosine Receptor Type 2A (A_2AAR) 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-A_2AAR. For the search for A_2AAR 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 A_2AAR.

Keywords: adenosine A2A receptor; molecular insight; virtual screening.

MeSH terms

Adenosine / analogs & derivatives
Adenosine / pharmacology
Adenosine A2 Receptor Agonists / pharmacology
Humans
Ligands
Molecular Docking Simulation / methods
Molecular Dynamics Simulation
Quantitative Structure-Activity Relationship
Receptors, Adenosine A2 / metabolism*

Substances

Adenosine A2 Receptor Agonists
Ligands
Receptors, Adenosine A2
UK-432097
Adenosine