Document Report Card

ID: ALA2029309

Journal: ACS Med Chem Lett

Title: Proposed Bioactive Conformations of Opiorphin, an Endogenous Dual APN/NEP Inhibitor.

Authors: Pinto M, Rougeot C, Gracia L, Rosa M, García A, Arsequell G, Valencia G, Centeno NB.

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.

CiteXplore: 24900367

DOI: 10.1021/ml200182v