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

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.

Antihypertensive effect and underlying mechanism of tripeptide NCW on spontaneously hypertensive rats using metabolomics analysis

“…40 Aldosterone synthase (CYP11B2), one of the broad cytochrome P450 family, regulates the synthesis of aldosterone from cholesterol in the reninangiotensin-aldosterone system. 41,42 Research by Wu et al also revealed the decreased aldosterone level and the increased corticosterone level may allow corticosterone to occupy the type I receptors more easily and increase BP. 43 Additionally, CDCA, DCA, and LCA could induce the mRNA and protein expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by stimulation of NF-κB and p38 MAPK signaling pathways, thereby causing endothelial dysfunction.…”

Protective Effects of Aqueous Extracts of the Herb of Paederia scandens (Lour.) Merr. against HCl/EtOH-Induced Gastric Ulcer in Rats: Involvement and Inhibitors’ Identification of NF-κB Signaling

“…In recent years, molecular simulation technologies such as pharmacophore model and molecular docking have been utilized for new drug research and development [44,45]. Te HipHop model is used to identify chemical features common to a range of small ligand molecules and automatically generates pharmacophore models based on the superposition of these common characteristic structures; ligand-based pharmacophore strategy has been universally used to screen small molecule-leading compounds in drug development [46].…”

Using Coexpression Protein Interaction Network Analysis to Identify Mechanisms of Danshensu Affecting Patients with Coronary Heart Disease

“…Based on more than 100 pharmacophore models constructed previously by our laboratory [ 37 , 38 , 39 , 40 , 41 ], the ones matched with DSS were searched and their Fit values compared to the chemical structure of DSS were calculated. The proteins corresponding to pharmacophore models with Fit value >0.7 were selected as source proteins used in the following study [ 42 ].…”