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Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode.
Lagarias, Panagiotis; Vrontaki, Eleni; Lambrinidis, George; Stamatis, Dimitrios; Convertino, Marino; Ortore, Gabriella; Mavromoustakos, Thomas; Klotz, Karl-Norbert; Kolocouris, Antonios.
Afiliação
  • Lagarias P; Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
  • Vrontaki E; Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
  • Lambrinidis G; Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
  • Stamatis D; Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
  • Convertino M; Department of Biochemistry & Biophysics , University of North Carolina at Chapel Hill , 120 Mason Farm Road , Chapel Hill , North Carolina 27599 , United States.
  • Ortore G; Department of Pharmacy , University of Pisa , 56126 Pisa , Italy.
  • Mavromoustakos T; Division of Organic Chemistry, Department of Chemistry, School of Science , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
  • Klotz KN; Institute of Pharmacology and Toxicology , University of Würzburg Versbacher Str. 9 , 97078 Würzburg , Germany.
  • Kolocouris A; Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences , National and Kapodistrian University of Athens , Panepistimiopolis-Zografou , 15771 Athens , Greece.
J Chem Inf Model ; 58(4): 794-815, 2018 04 23.
Article em En | MEDLINE | ID: mdl-29485875
An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A2A and A1ARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinder library of 14400 compounds was utilized to apply a combination of structure-based against the crystal structure of A2AAR and ligand-based methodologies. The docking poses were rescored by CHARMM energy minimization and calculation of the desolvation energy using Poisson-Boltzmann equation electrostatics. Out of the eight selected and tested compounds, five were found positive hits (63% success). Although the project was initially focused on targeting A2AAR, the identified antagonists exhibited low micromolar or micromolar affinity against A2A/A3, ARs, or A3AR, respectively. Based on these results, 19 compounds characterized by novel chemotypes were purchased and tested. Sixteen of them were identified as AR antagonists with affinity toward combinations of the AR family isoforms (A2A/A3, A1/A3, A1/A2A/A3, and A3). The second part of this work involves the performance of hundreds of molecular dynamics (MD) simulations of complexes between the ARs and a total of 27 ligands to resolve the binding interactions of the active compounds, which were not achieved by docking calculations alone. This computational work allowed the prediction of stable and unstable complexes which agree with the experimental results of potent and inactive compounds, respectively. Of particular interest is that the 2-amino-thiophene-3-carboxamides, 3-acylamino-5-aryl-thiophene-2-carboxamides, and carbonyloxycarboximidamide derivatives were found to be selective and possess a micromolar to low micromolar affinity for the A3 receptor.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Purinérgicos P1 / Descoberta de Drogas / Simulação de Dinâmica Molecular / Antagonistas de Receptores Purinérgicos P1 Idioma: En Revista: J Chem Inf Model Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Grécia

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptores Purinérgicos P1 / Descoberta de Drogas / Simulação de Dinâmica Molecular / Antagonistas de Receptores Purinérgicos P1 Idioma: En Revista: J Chem Inf Model Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Grécia