title: Proposed Bioactive Conformations of Opiorphin, an Endogenous Dual APN/NEP Inhibitor.
abstract: The conformational profiles for the endogenous peptide Opiorphin and a set of seven analogues exhibiting different inhibitory activities toward human aminopeptidase N (hAPN) and human neprilysin (hNEP) were independently computed to deduce a bioactive conformation that Opiorphin may adopt when binding these two enzymes. The conformational space was thoroughly sampled using an iterative simulated annealing protocol, and a library of low-energy conformers was generated for each peptide. Bioactive Opiorphin conformations fitting our experimental structure-activity relationship data were identified for hAPN and hNEP using computational pairwise comparisons between each of the unique low-energy conformations of Opiorphin and its analogues. The obtained results provide a structural explanation for the dual hAPN and hNEP inhibitory activity of Opiorphin and show that the inborn flexibility of Opiorphin is essential for its analgesic activity.
authors.affiliation: Computer-Assisted Drug Design Laboratory, Research Programme on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra , Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pinto
authors.affiliation: Institut Pasteur-Unité de Biochimie Structurale et Cellulaire/URA2185-CNRS , 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rougeot
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College , 1300 York Avenue, New York, New York 10065, United States.
authors.forename: Luis
authors.initials: L
authors.lastname: Gracia
authors.affiliation: Unit of Glycoconjugate Chemistry, Instituto de Química Avanzada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Mònica
authors.initials: M
authors.lastname: Rosa
authors.affiliation: Computer-Assisted Drug Design Laboratory, Research Programme on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra , Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: García
authors.affiliation: Unit of Glycoconjugate Chemistry, Instituto de Química Avanzada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Arsequell
authors.affiliation: Unit of Glycoconjugate Chemistry, Instituto de Química Avanzada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, E-08034 Barcelona, Spain.
authors.forename: Gregorio
authors.initials: G
authors.lastname: Valencia
authors.affiliation: Computer-Assisted Drug Design Laboratory, Research Programme on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra , Dr. Aiguader 88, E-08003 Barcelona, Spain.
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
keywords: Opiorphin; bioactive conformation; conformational analysis