Molecular docking and pharmacophore models to probe binding hypothesis of inhibitors of hypoxia inducible factor-1

Hypoxia inducible factor 1 alpha (HIF-1α) regulates cell growth and differentiation which is implicated in human cancers. HIF-1α activates its cascade carcinogenesis mechanism in cancer cells. It is well-understood that signaling is initiated by HIF-1α receptor. Overexpression of HIF-1α is associated with several different human cancers, including breast cancer, lung cancer and colon cancer. Thus, HIF-1α becomes potential target of therapeutic approach in developing HIF-1α inhibitors. The aim of this research is to investigate potential inhibitors which are known as Acetogenins (AGEs) isolated from Annona muricata against HIF-1α. In order to achieve this goal, chemical structures of all compounds were retrieved from PubChem database. Molecular docking was performed by AutoDock Vina program and the resulting binding modes were analyzed with AutoDock Tools program. Among all the compounds, murihexocin A showed the best binding modes compared to other two inhibitors based on the lowest binding energies (LBE = -7.9 kcal/mol) as high as gefitinib. This was indicating that murihexocin A has favorable interaction with the essential amino acid residues at catalytic site of HIF-1α. Drug-likeness calculation of AGEs were also performed. These in silico results could be beneficial as a compound model for further studies in-vitro and in-vivo.

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Adhatoda Vasica: A Potential Ayurvedic Intervention Against COVID-19 Associated Impaired Immune Response and Hypoxia-Inflammation Phenotype

10.21203/rs.3.rs-105233/v1 ◽

2020 ◽

Author(s):

Atish Prabhakar Gheware ◽

Dhwani Dholakia ◽

S Kanan ◽

Lipsa Panda ◽

Vivek Anand ◽

...

Keyword(s):

Molecular Docking ◽

Viral Entry ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Hypoxia Inducible Factor ◽

Adhatoda Vasica ◽

Hypoxia Inducible Factor 1 ◽

Infection And Inflammation ◽

Impaired Immune Response ◽

Host Target

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. Methods: In this study we tested the effect of whole aqueous extract Adhatoda Vasica (AV), that our group has shown to have anti-hypoxic and anti-inflammatory effects, on various outcomes of hypoxic response. Effects of AV were assessed in preclinical mouse models of pulmonary fibrosis, bacterial sepsis and siRNA induced hypoxia-thrombosis phenotype. Therapeutic relevance of AV in current pandemic were also examined through transcriptome and molecular docking analysis. Results: Oral administration AV extract attenuated the increased levels of airway inflammation, collagen content, transforming growth factor-b1 (TGF-b1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated and Cecum Ligation and Puncture (CLP) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, TGF-b1 and angiogenesis and upregulation of adaptive immunity related genes. These genes and pathways show opposite expression in transcriptome of BALF and PBMCs of SARS-CoV2 infected patient. Molecular docking of AV constituents presents in extract reveal many molecules with low binding energy (≤ -8) to multiple SARS-CoV2 and host target proteins that are relevant in viral entry and replication. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features which could be useful against SARS-CoV-2 infection.

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Vascular adaptations to hypoxia: molecular and cellular mechanisms regulating vascular tone

Essays in Biochemistry ◽

10.1042/bse0430105 ◽

2007 ◽

Vol 43 ◽

pp. 105-120 ◽

Cited By ~ 8

Author(s):

Michael L. Paffett ◽

Benjimen R. Walker

Keyword(s):

Vascular Tone ◽

Cellular Proliferation ◽

Hypoxic Pulmonary Vasoconstriction ◽

Hypoxia Inducible Factor ◽

Systemic Circulation ◽

Cellular Mechanisms ◽

Hypoxia Inducible Factor 1 ◽

Pulmonary Vasoconstriction ◽

Adaptive Mechanisms ◽

Adaptive Processes

Several molecular and cellular adaptive mechanisms to hypoxia exist within the vasculature. Many of these processes involve oxygen sensing which is transduced into mediators of vasoconstriction in the pulmonary circulation and vasodilation in the systemic circulation. A variety of oxygen-responsive pathways, such as HIF (hypoxia-inducible factor)-1 and HOs (haem oxygenases), contribute to the overall adaptive process during hypoxia and are currently an area of intense research. Generation of ROS (reactive oxygen species) may also differentially regulate vascular tone in these circulations. Potential candidates underlying the divergent responses between the systemic and pulmonary circulations may include Nox (NADPH oxidase)-derived ROS and mitochondrial-derived ROS. In addition to alterations in ROS production governing vascular tone in the hypoxic setting, other vascular adaptations are likely to be involved. HPV (hypoxic pulmonary vasoconstriction) and CH (chronic hypoxia)-induced alterations in cellular proliferation, ionic conductances and changes in the contractile apparatus sensitivity to calcium, all occur as adaptive processes within the vasculature.

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Hypoxia Inducible Factor-1 (HIF-1) mediates trophoblast differentiation induced by oxygen tension and is overexpressed in preeclampsia

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86116-3 ◽

1998 ◽

Vol 5 (1) ◽

pp. 48A-48A

Author(s):

I CANIGGIA ◽

M KULISZEWSKI ◽

S LYE ◽

M POST

Keyword(s):

Oxygen Tension ◽

Hypoxia Inducible Factor ◽

Trophoblast Differentiation ◽

Hypoxia Inducible Factor 1

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TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

10.31234/osf.io/v24zc ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Human Lung Cancer ◽

Regulatory Subunit ◽

Patients With Cancer ◽

Hypoxia Inducible Factor 1 ◽

Chemically Induced ◽

Induced Tumors ◽

Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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