Angiotensin Converting Enzyme (ACE) inhibitors have been acknowledged as the first-line agents for the treatment of hypertension and a variety of cardiovascular disorders. The present study aims to develop Quantitative Structure-Activity Relationship (QSAR) models for a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the prediction of the activity of novel compounds as ACE inhibitors. Multiple Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish the QSAR between ACE inhibitory activities and molecular descriptors. The models generated by MLR and PLS analyses were comparable and demonstrated good predictive ability with statistical values of R2 = 0.76, F = 33.35 and s = 0.328 for MLR and statistical significance value of 0.536 and fraction of variance explained = 0.733 for PLS analysis. Cross-validated R2 values of 0.706 (for MLR) and 0.712 (for PLS) were obtained which indicates good internal predictive capacity of the models. Validation through external test set provided R2 values of 0.698 and 0.726 for the MLR and PLS analyses, respectively. The results obtained indicate the importance of steric (Verloop B1, K-alpha 3) hydrophobic (lipole Z component) and topological (Wiener index) descriptors in determining the activity of ACE inhibitors. Also, druggability of the compounds was checked by assessing the Lipinskis rule of five and no violation to this rule was found. The utility of this study is for the effective design of novel, more potent ACE inhibitors as it provides important information about the geometrical and structural requirements for the interaction of glycine derivatives with ACE.
Sarvesh Kumar Paliwal, Anubhuti Pandey and Shailendra Paliwal, 2011. Quantitative Structure Activity Relationship Analysis of N-(mercaptoalkanoyl)- and [(acylthio)alkanoyl] Glycine Derivatives as ACE Inhibitors. American Journal of Drug Discovery and Development, 1: 85-104.