Discovery of prolyl hydroxylase 2 inhibitors with new chemical scaffolds as in vivo active erythropoietin inducers through a combined virtual screening strategy

AbstractEnolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids enolase was proposed as a key enzyme afterin silicoandin vivoanalysis and it was validated as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for further analysis, resulting in six compounds of medical use (etidronate, pamidronate, fosfomycin, acetohydroximate, triclofos, and aminohydroxybutyrate). Molecular docking simulations predicted acetohydroxamate and triclofos would not bind to the active site of the enzyme, and a re-scoring of the obtained poses signaled fosfomycin and aminohydroxybutyrate as bad enzyme binders. Docking poses obtained for etidronate, pamidronate, and PEP, were used for molecular dynamics calculations to describe their mode of binding. From the obtained results, we propose etidronate as a possibleTcENO inhibitor, and describe desirable and undesirable molecular motifs to be taken into account in the repurposing or design of drugs aiming this enzyme active site.

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Promising Anti-stroke Signature of Voglibose: Investigation through In- Silico Molecular Docking and Virtual Screening in In-Vivo Animal Studies

Current Gene Therapy ◽

10.2174/1566523220999200726225457 ◽

2020 ◽

Vol 20 (3) ◽

pp. 223-235

Author(s):

Pooja Shah ◽

Vishal Chavda ◽

Snehal Patel ◽

Shraddha Bhadada ◽

Ghulam Md. Ashraf

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

In Silico ◽

Reductase Activity ◽

Infarct Volume ◽

Docking Studies ◽

Serum Glucose ◽

In Vivo Studies ◽

In Silico Molecular Docking

Background: Postprandial hyperglycemia considered to be a major risk factor for cerebrovascular complications. Objective: The current study was designed to elucidate the beneficial role of voglibose via in-silico in vitro to in-vivo studies in improving the postprandial glycaemic state by protection against strokeprone type 2 diabetes. Material and Methods: In-Silico molecular docking and virtual screening were carried out with the help of iGEMDOCK+ Pymol+docking software and Protein Drug Bank database (PDB). Based on the results of docking studies, in-vivo investigation was carried out for possible neuroprotective action. T2DM was induced by a single injection of streptozotocin (90mg/kg, i.v.) to neonates. Six weeks after induction, voglibose was administered at the dose of 10mg/kg p.o. for two weeks. After eight weeks, diabetic rats were subjected to middle cerebral artery occlusion, and after 72 hours of surgery, neurological deficits were determined. The blood was collected for the determination of serum glucose, CK-MB, LDH and lipid levels. Brains were excised for determination of brain infarct volume, brain hemisphere weight difference, Na+-K+ ATPase activity, ROS parameters, NO levels, and aldose reductase activity. Results: In-silico docking studies showed good docking binding score for stroke associated proteins, which possibly hypotheses neuroprotective action of voglibose in stroke. In the present in-vivo study, pre-treatment with voglibose showed a significant decrease (p<0.05) in serum glucose and lipid levels. Voglibose has shown significant (p<0.05) reduction in neurological score, brain infarct volume, the difference in brain hemisphere weight. On biochemical evaluation, treatment with voglibose produced significant (p<0.05) decrease in CK-MB, LDH, and NO levels in blood and reduction in Na+-K+ ATPase, oxidative stress, and aldose reductase activity in brain homogenate. Conclusion: In-silico molecular docking and virtual screening studies and in-vivo studies in MCAo induced stroke, animal model outcomes support the strong anti-stroke signature for possible neuroprotective therapeutics.

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The pro-oncogenic adaptor CIN85 inhibits hypoxia-inducible factor prolyl hydroxylase-2

10.1101/466946 ◽

2018 ◽

Author(s):

Nina Kozlova ◽

Daniela Mennerich ◽

Anatoly Samoylenko ◽

Elitsa Y. Dimova ◽

Peppi Koivunen ◽

...

Keyword(s):

Tumor Growth ◽

Survival Function ◽

Hypoxia Inducible Factor ◽

Adaptor Protein ◽

Prolyl Hydroxylase ◽

Binding Partner ◽

And Migration ◽

Hif Prolyl Hydroxylase ◽

Promote Breast Cancer

SummaryThe EGFR-adaptor protein CIN85 has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill-defined. Here, we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SH3 domains of CIN85 interact with the proline-arginine rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF-degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9 edited cells affected growth and migration properties as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2, and uncovered an essential survival function in tumor cells linking growth factor adaptors with hypoxia signaling.

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Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates

International Journal of Medicinal Chemistry ◽

10.1155/2018/9139786 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11

Author(s):

Musab Mohamed Ibrahim ◽

Tilal Elsaman ◽

Mosab Yahya Al-Nour

Keyword(s):

Virtual Screening ◽

Condensation Reaction ◽

Docking Study ◽

Positive Control ◽

Inflammatory Activity ◽

Molecular Docking Study ◽

Design Synthesis ◽

Chemical Structures ◽

Anti Inflammatory

The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff’s bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff’s condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142).

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