Molecular dynamic simulations of full-length human purinergic receptor subtype P2X7 bonded to potent inhibitors.

Dos Santos, Eldio G; Faria, Robson X; Rodrigues, Carlos R; Bello, Murilo L

Dos Santos, Eldio G; Faria, Robson X; Rodrigues, Carlos R; Bello, Murilo L.

Afiliación

Dos Santos EG; Laboratório de Planejamento Farmacêutico e Simulação Computacional, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Faria RX; Laboratório de Toxoplasmose e outras Protozooses, Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil.
Rodrigues CR; ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Bello ML; Laboratório de Planejamento Farmacêutico e Simulação Computacional, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: murilolamim@pharma.ufrj.br.

Eur J Pharm Sci ; 152: 105454, 2020 Sep 01.

Article en En | MEDLINE | ID: mdl-32629018

RESUMEN

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.

Asunto(s)

Inflamación; Simulación de Dinámica Molecular; Adenosina Trifosfato; Aniones; Humanos; Ligandos; Receptores Purinérgicos P2X7; Triazoles

Palabras clave

Drug Design; Molecular dynamic; Naphthoquinone; P2X7; Triazole

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Simulación de Dinámica Molecular / Inflamación Límite: Humans Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Países Bajos

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