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Proposed Bioactive Conformations of Opiorphin, an Endogenous Dual APN/NEP Inhibitor
Marta Pinto1, Catherine Rougeot2, Luis Gracia3
1Computer-Assisted Drug Design Laboratory, Research Programme on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra , Dr. Aiguader 88, E-08003 Barcelona, Spain.
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.
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