scholarly journals Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xiaoqian Huo ◽  
Liansheng Qiao ◽  
Yankun Chen ◽  
Xi Chen ◽  
Yusu He ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Virtual Screening ◽  
Bos Taurus ◽  
Calcium Influx ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
At1 Antagonist ◽  
Neprilysin Inhibitor ◽  
Gyrophoric Acid

Abstract Angiotensin II type-1 receptor–neprilysin inhibitor (ARNi) is consisted of Angiotensin II type-1 receptor (AT1) antagonist and neprilysin (NEP) inhibitor, which could simultaneously increase the vasodilators of the natriuretic peptides and antagonize vasoconstrictors of Ang II. ARNi has been proved a superior effect and lower risks of death on chronic heart failure (CHF) and hypertension. In this paper, ARNi from Traditional Chinese Medicines (TCM) was discovered based on target combination of AT1 and NEP by virtual screening, biological assay and molecular dynamics (MD) simulations. Two customized strategies of combinatorial virtual screening were implemented to discover AT1 antagonist and NEP inhibitor based on pharmacophore modeling and docking computation respectively. Gyrophoric acid (PubChem CID: 135728) from Parmelia saxatilis was selected as AT1 antagonist and assayed with IC50 of 29.76 μM by calcium influx assay. And 3,5,3′-triiodothyronine (PubChem CID: 861) from Bos taurus domesticus was screened as NEP inhibitor and has a dose dependent inhibitory activity by biochemistry fluorescence assay. Combined with MD simulations, these compounds can generate interaction with the target, key interactive residues of ARG167, TRP84, and VAL108 in AT1, and HIS711 in NEP were also identified respectively. This study designs the combinatorial strategy to discover novel frames of ARNi from TCM, and gyrophoric acid and 3,5,3′-triiodothyronine could provide the clues and revelations of drug design and therapeutic method of CHF and hypertension for TCM clinical applications.

scholarly journals Molecular docking, pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori

RSC Advances ◽  
2019 ◽  
Vol 9 (45) ◽  
pp. 26176-26208 ◽  
Author(s):  
Manoj G. Damale ◽  
Rajesh B. Patil ◽  
Siddique Akber Ansari ◽  
Hamad M. Alkahtani ◽  
Abdulrahman A. Almehizia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Virtual Screening ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
Gastric Ulcers ◽  
Computational Approaches ◽  
Gastric Cancers ◽  
H Pylori

Computational approaches such as pharmacophore modeling, virtual screening and MD simulations were explored to find the potential hits as H. pylori specific panC inhibitors for the management of gastric ulcers and gastric cancers.

The angiotensin II type 1 receptor-neprilysin inhibitor LCZ696 blocked aldosterone synthesis in a human adrenocortical cell line

2016 ◽  
Vol 39 (11) ◽  
pp. 758-763 ◽  
Author(s):  
Shin-Ichiro Miura ◽  
Yasunori Suematsu ◽  
Yoshino Matsuo ◽  
Sayo Tomita ◽  
Asuka Nakayama ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cell Line ◽  
Adrenocortical Cell ◽  
Neprilysin Inhibitor

Effects of angiotensin II on the acrosome reaction in equine spermatozoa

Reproduction ◽  
2000 ◽  
pp. 135-142 ◽  
Author(s):  
K Sabeur ◽  
AT Vo ◽  
BA Ball
Keyword(s):  
Angiotensin Ii ◽  
Acrosome Reaction ◽  
Calcium Influx ◽  
Fluorescein Isothiocyanate ◽  
Major Sperm Protein ◽  
Hoechst 33258 ◽  
Sperm Protein ◽  
Acrosomal Exocytosis

Angiotensin II is a hormone with a wide array of physiological effects that exerts its effect via interaction with two major subtypes of receptor. The results of this study show that angiotensin II (from 1 to 100 nmol l(-1)) initiates acrosomal exocytosis in equine spermatozoa that have undergone capacitation in vitro in a TALP-TEST (Tyrode's albumin lactate pyruvate; 188.7 mmol TES l(-1), 84.8 mmol Tris l(-1)) buffer with cAMP. The acrosome reaction and sperm viability were assessed with fluorescein isothiocyanate-Pisum sativum agglutinin (FITC-PSA) and Hoechst 33258, respectively. The initiation of the acrosome reaction by angiotensin II was strongly inhibited by losartan, a specific angiotensin II type 1 receptor antagonist. Although angiotensin II as well as progesterone both initiated the acrosome reaction in equine spermatozoa, there was no synergistic effect when both agonists were added simultaneously. Initiation of acrosomal exocytosis by angiotensin II was accompanied by a rapid and transient calcium influx that was assessed in capacitated spermatozoa loaded with Fura-2AM. In addition, the angiotensin II-mediated calcium influx was inhibited when spermatozoa were preincubated with losartan. Western blotting with an antibody against angiotensin II type 1 receptor detected a major sperm protein of 60 kDa. Indirect immunofluorescence of non-capacitated spermatozoa with the angiotensin II type 1 receptor antibody revealed labelling in the midpiece and tail. In capacitated spermatozoa, the angiotensin II type 1 receptor was localized mainly over the anterior region of the sperm head, the equatorial segment and occasionally on the postacrosomal region in addition to the sperm tail. In conclusion, this study demonstrated the ability of angiotensin II to stimulate the acrosome reaction in capacitated equine spermatozoa. This effect is mediated via the angiotensin II type 1 receptor and is accompanied by an increase in intracellular calcium.

scholarly journals Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5914-5920 ◽  
Author(s):  
Hiroyuki Suzuki ◽  
Kunie Eguchi ◽  
Haruhiko Ohtsu ◽  
Sadaharu Higuchi ◽  
Sudhir Dhobale ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Enos Gene ◽  
No Production ◽  
Hypertrophic Response ◽  
Cgmp Production ◽  
At1 Antagonist

Enhanced angiotensin II (AngII) action has been implicated in endothelial dysfunction that is characterized as decreased nitric oxide availability. Although endothelial cells have been reported to express AngII type 1 (AT1) receptors, the exact role of AT1 in regulating endothelial NO synthase (eNOS) activity remains unclear. We investigated the possible regulation of eNOS through AT1 in bovine aortic endothelial cells (BAECs) and its functional significance in rat aortic vascular smooth muscle cells (VSMCs). In BAECs infected with adenovirus encoding AT1 and in VSMCs infected with adenovirus encoding eNOS, AngII rapidly stimulated phosphorylation of eNOS at Ser1179. This was accompanied with increased cGMP production. These effects were blocked by an AT1 antagonist. The cGMP production was abolished by a NOS inhibitor as well. To explore the importance of eNOS phosphorylation, VSMCs were also infected with adenovirus encoding S1179A-eNOS. AngII did not stimulate cGMP production in VSMCs expressing S1179A. However, S1179A was able to enhance basal NO production as confirmed with cGMP production and enhanced vasodilator-stimulated phosphoprotein phosphorylation. Interestingly, S1179A prevented the hypertrophic response similar to wild type in VSMCs. From these data, we conclude that the AngII/AT1 system positively couples to eNOS via Ser1179 phosphorylation in ECs and VSMCs if eNOS and AT1 coexist. However, basal level NO production may be sufficient for prevention of AngII-induced hypertrophy by eNOS expression. These data demonstrate a novel molecular mechanism of eNOS regulation and function and thus provide useful information for eNOS gene therapy under endothelial dysfunction.

The Discovery of New 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors by Common Feature Pharmacophore Modeling and Virtual Screening

2006 ◽  
Vol 49 (12) ◽  
pp. 3454-3466 ◽  
Author(s):  
Daniela Schuster ◽  
Evelyne M. Maurer ◽  
Christian Laggner ◽  
Lyubomir G. Nashev ◽  
Thomas Wilckens ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Hydroxysteroid Dehydrogenase ◽  
Pharmacophore Modeling

scholarly journals Aldosterone mediates angiotensin II-stimulated rat vascular smooth muscle cell proliferation

2000 ◽  
Vol 165 (2) ◽  
pp. 533-536 ◽  
Author(s):  
F Xiao ◽  
GP Vinson ◽  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Cellular Proliferation ◽  
Muscle Cells ◽  
Treated Group ◽  
Aortic Smooth Muscle ◽  
At1 Antagonist

Aldosterone, possibly locally generated, has been suggested to have a role in potentiating angiotensin II (AII)-stimulated hypertrophy of cultured vascular smooth muscle cells. To examine the possibility that aldosterone may mediate the proliferative actions of AII, rat aortic smooth muscle cells (RASMCs) in culture were treated with AII in the presence and absence of the specific AII type 1 receptor (AT1) antagonist, losartan, and aldosterone was assayed in culture medium extracts by radioimmunoassay. AII significantly enhanced aldosterone formation (at 10(-8) M: 123.8+/-14.85 vs control 71. 28+/- 8.71 fmol/10(5) cells, P<0.05; at 10(-7) M: 172.38+/-33.44, P<0.05), but not in the presence of losartan (at 10(-8) M: 53. 71+/-18.73, P>0.05; at 10(-7) M: 89.68+/-25.05, P>0.05). In other studies, the reverse transcriptase-polymerase chain reaction, performed on RNA extracted from RASMCs using aldosterone synthase (CYP11B2) specific primers, gave a single band of about 268 bp, consistent with that expected for the enzyme. Finally, using [(3)H]methylthymidine uptake as an index of cellular proliferation, tritium incorporation was increased in the AII-treated group at concentrations greater than 10(-10) M. The aldosterone antagonist, spironolactone (10(-5) M), inhibited the incorporation of [(3)H]thymidine into RASMCs stimulated by AII. These results suggest that locally generated aldosterone may mediate the effects of AII, acting via the AT1 receptor, in stimulating RASMC proliferation.

Structural Insight on the Activity of Type 1 Angiotensin II Peptide Antagonists Using MD Simulations

2008 ◽  
Vol 112 (43) ◽  
pp. 13620-13628
Author(s):  
Marco A. C. Preto ◽  
André Melo ◽  
Lígia M. Rodrigues ◽  
Hernâni L. S. Maia ◽  
Maria J. Ramos
Keyword(s):  
Angiotensin Ii ◽  
Md Simulations ◽  
Structural Insight

scholarly journals Insights into the Interaction of LVV-Hemorphin-7 with Angiotensin II Type 1 Receptor

2020 ◽  
Vol 22 (1) ◽  
pp. 209
Author(s):  
Amanat Ali ◽  
Elizabeth K. M. Johnstone ◽  
Bincy Baby ◽  
Heng B. See ◽  
Angela Song ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Angiotensin Ii ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Md Simulations ◽  
Hek293 Cells ◽  
Renal Physiology ◽  
Binding Behavior ◽  
Intracellular Loops

Hemorphins are known for their role in the control of blood pressure. Recently, we revealed the positive modulation of the angiotensin II (AngII) type 1 receptor (AT1R) by LVV-hemorphin-7 (LVV-H7) in human embryonic kidney (HEK293) cells. Here, we examined the molecular binding behavior of LVV-H7 on AT1R and its effect on AngII binding using a nanoluciferase-based bioluminescence resonance energy transfer (NanoBRET) assay in HEK293FT cells, as well as molecular docking and molecular dynamics (MD) studies. Saturation and real-time kinetics supported the positive effect of LVV-H7 on the binding of AngII. While the competitive antagonist olmesartan competed with AngII binding, LVV-H7 slightly, but significantly, decreased AngII’s kD by 2.6 fold with no effect on its Bmax. Molecular docking and MD simulations indicated that the binding of LVV-H7 in the intracellular region of AT1R allosterically potentiates AngII binding. LVV-H7 targets residues on intracellular loops 2 and 3 of AT1R, which are known binding sites of allosteric modulators in other GPCRs. Our data demonstrate the allosteric effect of LVV-H7 on AngII binding, which is consistent with the positive modulation of AT1R activity and signaling previously reported. This further supports the pharmacological targeting of AT1R by hemorphins, with implications in vascular and renal physiology.

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