1. Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches
- Author
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Rosivaldo S. Borges, Luciane B. Silva, Jorddy Neves Cruz, Sirlene S. B. Ota, Kelton L. B. Santos, Franco Henrique Andrade Leite, Moysés Fagundes de Araújo Neto, Carlos Henrique Tomich de Paula da Silva, Ryan da Silva Ramos, Joaquín M. Campos, Cleison C. Lobato, Cleydson B. R. Santos, [Dos Santos,KLB, Cruz,JN, Silva,LB, Ramos,RS, Lobato,CC, Borges,RS, Santos,CBR] Laboratory of Modeling and Computational Chemistry, Department of Biological and Health Sciences, Federal University of Amapá, Macapá-AP, Brazil. [Dos Santos,KLB, Ota,SSB, Santos,CBR] Nucleus of Studies and Selection of Bioactive Molecules, Institute of Health Sciences, Federal University of Pará, Belém-PA, Brazil. [Neto,MFA, Leite,FHA, and ] Laboratory of Molecular Modeling, State University of Feira de Santana, Feira de Santana, Bahia, Brazil. [da SIlva,CHTP] Computational Laboratory of Pharmaceutical Chemistry, University of São Paulo, Ribeirão Preto-SP, Brazil. [da SIlva,CHTP] Department of Chemistry, Faculty of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil. [Campos,JM] Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Institute of Biosanitary, Research ibs. Granada, University of Granada, Granada, Spain.
- Subjects
Adenosine ,Molecular model ,Pharmaceutical Science ,Quantitative Structure-Activity Relationship ,Relación estructura-actividad cuantitativa ,Ligands ,Chemicals and Drugs::Chemical Actions and Uses::Specialty Uses of Chemicals::Laboratory Chemicals::Ligands [Medical Subject Headings] ,Analytical Chemistry ,Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Structure-Activity Relationship::Quantitative Structure-Activity Relationship [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Molecular dynamics ,Simulación del acoplamiento molecular ,Drug Discovery ,Agonistas del receptor de adenosina A2 ,0303 health sciences ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular::Molecular Dynamics Simulation [Medical Subject Headings] ,Chemistry ,Biological activity ,Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Purines::Purine Nucleosides::Adenosine [Medical Subject Headings] ,Molecular Docking Simulation ,INDÚSTRIA FARMACÊUTICA ,Cribado sistemático ,Chemistry (miscellaneous) ,Molecular Medicine ,BindingDB ,Pharmacophore ,Virtual screening ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Purinergic::Receptors, Purinergic P1::Receptors, Adenosine A2 [Medical Subject Headings] ,Quantitative structure–activity relationship ,Adenosine A2 Receptor Agonists ,030303 biophysics ,Computational biology ,Adenosine A2A receptor ,Molecular Dynamics Simulation ,Article ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Molecular::Molecular Docking Simulation [Medical Subject Headings] ,Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Neurotransmitter Agents::Purinergic Agents::Purinergic Agonists::Purinergic P1 Receptor Agonists::Adenosine A2 Receptor Agonists [Medical Subject Headings] ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Molecular insight ,Humans ,Physical and Theoretical Chemistry ,030304 developmental biology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Purinergic::Receptors, Purinergic P1 [Medical Subject Headings] ,adenosine A2A receptor ,Receptors, Adenosine A2 ,Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Statistical::Linear Models [Medical Subject Headings] ,Organic Chemistry ,virtual screening ,Simulación de Dinámica Molecular ,Docking (molecular) ,molecular insight - Abstract
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, PROPESP/UFPA, National Council for Scientific and Technological Development (CNPq)
- Published
- 2020