Insight into structural requirements of ACE inhibitory dipeptides: QSAR and molecular docking studies
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ORIGINAL ARTICLE
Insight into structural requirements of ACE inhibitory dipeptides: QSAR and molecular docking studies Fangfang Wang1 · Bo Zhou2 Received: 22 September 2019 / Accepted: 16 October 2019 © Springer Nature Switzerland AG 2019
Abstract The angiotensin I-converting enzyme (ACE) has been found to exhibit inhibitory capability against blood pressure. Recently, several ACE inhibitors with different structures have been reported. In the present work, molecular modeling studies using quantitative structure–activity relationship (QSAR) and molecular docking simulations were carried out. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were firstly used to generate 3D-QSAR models. The results indicate that the best CoMFA model has R2cv = 0.504, R2pred = 0.5896, and the best CoMSIA model has R2cv = 0.525, R2pred = 0.5666. Furthermore, 2D-QSAR models developed by multiple linear regression/ MLR, partial least squares regression/PLSR, and support vector machine regression/SVR methods provide highly significant squared correlation coefficient R2tr values of 0.8380, 0.8650, and 0.8230, external validated correlation coefficient Q2te of 0.8279, 0.8223, and 0.7255, respectively. The statistical results show satisfactory goodness-of-fit, robustness, and perfect external predictive performance. Moreover, molecular docking studies were employed to predict the binding mode between dipeptides and ACE receptor. The combination of QSAR studies and molecular docking indicates the requirement of certain physicochemical parameters for better ACE inhibitors. Graphic abstract
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Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11030-019-10005-0) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Molecular Diversity
Keywords The angiotensin I-converting enzyme · CoMFA · CoMSIA · Molecular docking
Introduction Cardiovascular disease (CVD) has been regarded as the leading cause of death in the worldwide, with characteristics of frequent, chronic, and age-related disorders [1, 2]. In addition, CVD can be originated from hypertension [3]. Studies have shown that blood pressure-lowering therapy can be used to treat CVD [4]. In the process of blood pressure regulation, angiotensin I-converting enzyme (ACE) appertaining to the class of zinc protease plays a vital role in the renin–angiotensin system (RAS) and kallikrein–kinin system (KKS) which would control blood pressure by converting angiotensin I into a powerful vasoconstrictor angiotensin II [5, 6]. Therefore, ACE is considered to be the main target for the prevention and treatment of hypertension and associated diseases. Recently, some synthetic ACE inhibitors, such as captopril, enalapril, and lisinopril, have been employed as antihypertensive agents [7]. However, these inhibitors may lead to several side effects, i
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