Receptor-based 3D-QSAR study for recognizing true binding mode of mercaptoacyldipeptides at the active site of neutral endopeptidase.

摘要

Among neutral endopeptidase (NEP) inhibitors, mercaptoacyldipeptides implicated in cardiovascular diseases, are of great interest. Two groups, Coric et al. and Oefner et al. described two different binding preferences for mercaptoacyldipeptides at the active site of NEP. By focusing on both, 3D-QSAR studies were performed on mercaptoacyldipeptides, based on conformational alignment obtained by GOLD 3.2, using CoMFA and CoMSIA techniques. Statistically significant 3D-QSAR models were obtained with q2 of 0.580 and 0.559, and r2 of 0.996 and 0.991, respectively. Both the models were validated by an external test set of nine compounds giving highly predictive r2(pred) of 0.929 and 0.928, respectively. The study will facilitate the rational design of more potent mercaptoacyldipeptides for the treatment of cardiovascular diseases.