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Tipo
ArtículoDerechos de autor
Acceso restringido
Fecha del embargo
2023
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- IOC - Artigos de Periódicos [12642]
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MOLECULAR DYNAMIC SIMULATIONS OF FULL-LENGTH HUMAN PURINERGIC RECEPTOR SUBTYPE P2X7 BONDED TO POTENT INHIBITORS
Afiliación
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Planejamento Farmacêutico e Simulação Computacional. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e outras Protozooses. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. ModMolQSAR. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Planejamento Farmacêutico e Simulação Computacional. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Toxoplasmose e outras Protozooses. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. ModMolQSAR. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Laboratório de Planejamento Farmacêutico e Simulação Computacional. Rio de Janeiro, RJ, Brasil.
Resumen en ingles
Among the members of purinergic receptors, the family P2X of ionotropic proteins has the ion channel subtype
P2X7 that show in studies to be an important molecular target for new drugs. The activity of human P2X7
receptor (hP2X7r) in the body, due to its pro-inflammatory function, can trigger physiological disorders related
to chronic inflammatory processes, leading to neural degeneration, neuropathic pain and chronic pain. Recently,
two series of promising new inhibitors of the hP2X7r ion channel have been reported. One series consisted of
naphthoquinone derivatives and the other composed of triazole derivatives. The main objective of this study was
to understand the binding mode differences between the hit compounds of each series and compare them to the
native ligand ATP. The hP2X7r ion channel and membrane lipid models were prepared in order to allow study
the appropriate protein molecular dynamics. Molecular modeling and molecular dynamics simulation approaches
were applied in order to obtain atomistic and molecular details that are involved in intermolecular
interactions. Both compounds AN-04 and 9d seem to have affinity to binding in the hP2X7r pore area according
to molecular dynamics simulations results. The naphthoquinone derivative AN-04 demonstrated a binding free
energy 7.68 fold larger than triazole derivative 9d and 3.8 fold lower than native ligand ATP. These results
indicate that compound AN-04 might be a promising lead compound for the development of a novel selective
hP2X7r inhibitor.
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