Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies.

Ganggang Luo,Xi Chen,Yanling Zhang,Liansheng Qiao,Gongyu Li,Fang Lu

doi:10.1155/2016/4182595

Ganggang Luo, Xi Chen + Show 4 more

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https://doi.org/10.1155/2016/4182595

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Abstract

Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment.

Highlights

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, including coronary artery diseases (CAD), hypertensive, heart disease, stroke, cardiomyopathy, endocarditis, heart arrhythmia, aortic aneurysms, and peripheral artery disease [1, 2]
Aldosterone, the main mineralocorticoid hormone, is part of the renin-angiotensinaldosterone system (RAAS) [5], which plays a significant role in the regulation of blood pressure by increasing blood pressure and blood volume
Aldosterone synthase (CYP11B2) is a steroid hydroxylase cytochrome P450 enzyme [6], which is the key enzyme responsible for the production of aldosterone in humans. It accelerates the terminal three oxidation steps in synthetic pathway of aldosterone. It is a member of the cytochrome P450 superfamily of enzymes and plays an important role in electrolyte balance and blood pressure and catalyzes many reactions in the regulation of drug metabolism and synthesis of cholesterol, steroids, and other lipids

Summary

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide, including coronary artery diseases (CAD), hypertensive, heart disease, stroke, cardiomyopathy, endocarditis, heart arrhythmia, aortic aneurysms, and peripheral artery disease [1, 2]. Among these diseases, hypertension is a high-incidence cardiovascular disease around the world, leading to 7 million deaths each year and about 25% of adults suffer from the disease [3]. Aldosterone synthase (CYP11B2) is a steroid hydroxylase cytochrome P450 enzyme [6], which is the key enzyme responsible for the production of aldosterone in humans It accelerates the terminal three oxidation steps in synthetic pathway of aldosterone. It is a member of the cytochrome P450 superfamily of enzymes and plays an important role in electrolyte balance and blood pressure and catalyzes many reactions in the regulation of drug metabolism and synthesis of cholesterol, steroids, and other lipids

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