Abstract
Dilated cardiomyopathy is a disease of left ventricular dysfunction accompanied by impairment of the β1-adrenergic receptor (β1-AR) signal cascade. The disturbed β1-AR function may be based on an elevated sympathetic tone observed in patients with heart failure. Prolonged adrenergic stimulation may induce metabolic and electrophysiological disturbances in the myocardium, resulting in tachyarrhythmia that leads to the development of heart failure in human and sudden death. Hence, β1-AR is considered as a promising drug target but attempts to develop effective and specific drug against this tempting pharmaceutical target is slowed down due to the lack of 3D structure of Homo sapiens β1-AR (hsβADR1). This study encompasses elucidation of 3D structural and physicochemical properties of hsβADR1 via threading-based homology modeling. Furthermore, the docking performance of several docking programs including Surflex-Dock, FRED, and GOLD were validated by re-docking and cross-docking experiments. GOLD and Surflex-Dock performed best in re-docking and cross docking experiments, respectively. Consequently, Surflex-Dock was used to predict the binding modes of four hsβADR1 agonists. This study provides clear understanding of hsβADR1 structure and its binding mechanism, thus help in providing the remedial solutions of cardiovascular, effective treatment of asthma and other diseases caused by malfunctioning of the target protein.
Highlights
G-protein coupled receptor (GPCR) superfamily constitutes the largest family of receptors in cell responsible for mediating the effects of over 50% of drugs in the market now-a-days [1,2,3,4,5,6,7,8]
Such type of activated β1-adrenergic receptor (β1-AR) results in an increased cardiac inotropy, lusitropy, and chronotropy and the secretion of rennin, all of which contribute to regulate the cardiac functions and blood pressure [9,10]. β1-AR predominates in the heart, representing about 80% of the myocardial β-adrenergic receptors (β-ARs); they tend to be viewed as the most significant β-ARs with respect to the cardiovascular system. β1- and β2-ARs in kidneys stimulate the release of renin, thereby playing a role in the activation of renin-angiotensin-aldosterone system [9,10]
The results showed that the conformation of each ligand generated by Surflex-Dock is much better than the docked conformations generated by GOLD and FRED
Summary
G-protein coupled receptor (GPCR) superfamily constitutes the largest family of receptors in cell responsible for mediating the effects of over 50% of drugs in the market now-a-days [1,2,3,4,5,6,7,8]. Class A GPCRs is the largest group and encompasses a wide range of receptors including receptors for odorants, adenosine, β-adrenergic and Rhodopsin [1,2,3,4,5,6,7,8]. The β-adrenergic receptors (β-ARs) are Gs protein–coupled receptors that play important roles in cardiovascular function and disease, through serving as receptors for the neurohormones: norepinephrine and epinephrine. The rise in the intracellular [cAMP] level causes the phosphorylation of several intracellular proteins by means of cAMP-dependent protein kinase A. Such type of activated β1-AR results in an increased cardiac inotropy, lusitropy, and chronotropy and the secretion of rennin, all of which contribute to regulate the cardiac functions and blood pressure [9,10]. Such type of activated β1-AR results in an increased cardiac inotropy, lusitropy, and chronotropy and the secretion of rennin, all of which contribute to regulate the cardiac functions and blood pressure [9,10]. β1-AR predominates in the heart, representing about 80% of the myocardial β-ARs; they tend to be viewed as the most significant β-ARs with respect to the cardiovascular system. β1- and β2-ARs in kidneys stimulate the release of renin, thereby playing a role in the activation of renin-angiotensin-aldosterone system [9,10]
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