Pinto Marta, Rougeot Catherine, Gracia Luis, Rosa Mònica, García Andrés, Arsequell Gemma, Valencia Gregorio, Centeno Nuria B
Computer-Assisted Drug Design Laboratory, Research Programme on Biomedical Informatics (GRIB), IMIM-Universitat Pompeu Fabra , Dr. Aiguader 88, E-08003 Barcelona, Spain.
Institut Pasteur-Unité de Biochimie Structurale et Cellulaire/URA2185-CNRS , 25 rue du Docteur Roux, 75724 Paris Cedex 15, France.
ACS Med Chem Lett. 2011 Nov 17;3(1):20-4. doi: 10.1021/ml200182v. eCollection 2012 Jan 12.
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.
对内源性肽鸦片肽以及一组对人氨肽酶N（hAPN）和人中性肽链内切酶（hNEP）表现出不同抑制活性的七种类似物的构象分布进行了独立计算，以推断鸦片肽在结合这两种酶时可能采用的生物活性构象。使用迭代模拟退火协议对构象空间进行了全面采样，并为每种肽生成了低能构象库。通过对鸦片肽及其类似物的每个独特低能构象之间进行计算成对比较，确定了符合我们实验构效关系数据的hAPN和hNEP的生物活性鸦片肽构象。所得结果为鸦片肽对hAPN和hNEP的双重抑制活性提供了结构解释，并表明鸦片肽固有的灵活性对其镇痛活性至关重要。
