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Exploring the PDE5 H-pocket by ensemble docking and structure-based design and synthesis of novel ß-carboline derivatives.
Ahmed, Nermin S; Ali, Amal H; El-Nashar, Shreen M; Gary, Bernard D; Fajardo, Alexandra M; Tinsley, Heather N; Piazza, Gary A; Negri, Matthias; Abadi, Ashraf H.
Afiliação
  • Ahmed NS; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Main Entrance, Al-Tagmoaa Al-Khames, Cairo 11835, Egypt.
Eur J Med Chem ; 57: 329-43, 2012 Nov.
Article em En | MEDLINE | ID: mdl-23117589
By studying the co-crystal information of interactions between PDE5 and its inhibitors, forty new tetrahydro-ß-carbolines based-analogues were synthesized, and tested for their PDE5 inhibition. Some compounds were as active as tadalafil in inhibiting PDE5 and of better selectivity profile particularly versus PDE11A, the nature of the terminal ring and its nitrogen substituent are the main determinants of selectivity. Ensemble docking confirmed the role of H-loop closed conformer in activity versus its occluded and open forms. Conformational studies showed the effect of bulkiness of the terminal ring N-alkyl substituent on the formation of stable enzyme ligands conformers. The difference in potencies of hydantoin and piperazinedione analogues, together with the necessity of C-5/C-6 R-absolute configuration has been revealed through molecular docking.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carbolinas / Dicetopiperazinas / Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 / Inibidores da Fosfodiesterase 5 / Hidantoínas Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Carbolinas / Dicetopiperazinas / Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 / Inibidores da Fosfodiesterase 5 / Hidantoínas Limite: Humans Idioma: En Revista: Eur J Med Chem Ano de publicação: 2012 Tipo de documento: Article