In silico evaluation of NO donor heterocyclic vasodilators as SARS-CoV-2 Mpro protein inhibitor

2021 ◽  
pp. 1-18
Author(s):  
Abdullah G. Al-Sehemi ◽  
Rishikesh S. Parulekar ◽  
Mehboobali Pannipara ◽  
Manzur Ali P P ◽  
Pudukulathan K. Zubaidha ◽  
...  
Keyword(s):  
In Silico ◽  
Protein Inhibitor ◽  
No Donor

scholarly journals Potential of NO donor furoxan as SARS-CoV-2 main protease (Mpro) inhibitors: in silico analysis

2020 ◽  
pp. 1-15 ◽  
Author(s):  
Abdullah G. Al-Sehemi ◽  
Mehboobali Pannipara ◽  
Rishikesh S. Parulekar ◽  
Omkar Patil ◽  
Prafulla B. Choudhari ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
No Donor ◽  
Main Protease ◽  
Silico Analysis

Abstract 13295: Novel Experimental Therapeutics for COVID-19 Derived From a Nitric Oxide Donor

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
John F Schmedtje ◽  
Zahra Assar
Keyword(s):  
Nitric Oxide ◽  
Protein Interactions ◽  
In Silico ◽  
Vascular Endothelial Cells ◽  
Specific Binding ◽  
Nitric Oxide Donor ◽  
Isosorbide Mononitrate ◽  
Vascular Endothelial ◽  
No Donor ◽  
Glide Docking

Urea transport protein B, the product of the gene SLC14A1 , facilitates transport of urea, water and urea analogues across cell membranes. SLC14A1 mRNA is overexpressed in human vascular endothelial cells in culture under hypoxic (1% oxygen) conditions compared with normoxia. This leads to transport of urea out of the endothelial cell and likely contributes to the reduction in eNOS (endothelial nitric oxide synthase) pathway activity in hypoxia. NO has antiviral activity. Novel compounds were developed by binding a urea-like moiety to the backbone of the generic agent isosorbide mononitrate, a well-known NO donor, to combat vascular endothelial dysfunction in COVID-19, a disease characterized by systemic hypoxia and inflammation due to SARS-CoV-2 infection. A study of drug-protein interactions was undertaken using in silico modelling. Novel compounds were studied against 9 key SARS-CoV-2 targets using Maestro, Schrödinger Suite software (Glide docking). Docking scores and intermolecular interactions within the target’s key binding amino acid residues were studied to compare investigational compounds and known antivirals. Several novel agents tested had a better Glide Score (a prediction of ligand affinity) against the papain-like protease (PL pro ) of SARS-CoV-2 compared with known antiviral drugs. PL pro is considered to be a primary target for therapeutic inhibition of the SARS viruses. The candidate compounds CR-305, CR-607, CR-510 and CR-605 were all superior to Remdesivir, GS-441524, Lopinavir, Boceprevir, and Ribavirin. Given the known direct antiviral action of NO and evidence of specific binding of these compounds to the PL pro of SARS-CoV-2 based on the in silico results, we conclude there is a high likelihood these novel compounds will prove to be of therapeutic value against COVID-19. CR-305 appears to have a higher affinity to SARS-CoV-2 than other antivirals as it sits firmly in the PL pro catalytic pocket and makes the most of key interactions with the catalytic pocket residues: Gly163, Asp164, Gln271 and Tyr264. These data call for a new focus on these novel antiviral agents as they appear to bind with an increased avidity to PL pro (compared with other known antivirals) while targeting delivery of NO to the SARS-CoV-2 virus in COVID-19.

scholarly journals NO● Represses the Oxygenation of Arachidonoyl PE by 15LOX/PEBP1: Mechanism and Role in Ferroptosis

2021 ◽  
Vol 22 (10) ◽  
pp. 5253
Author(s):  
Karolina Mikulska-Ruminska ◽  
Tamil S. Anthonymuthu ◽  
Anastasia Levkina ◽  
Indira H. Shrivastava ◽  
Oleksandr O. Kapralov ◽  
...  
Keyword(s):  
In Silico ◽  
Functional Significance ◽  
Catalytic Site ◽  
Saturation Mutagenesis ◽  
M2 Macrophages ◽  
Modeling And Simulations ◽  
Biochemical System ◽  
No Donor ◽  
M1 Macrophages ◽  
Biochemical Model

We recently discovered an anti-ferroptotic mechanism inherent to M1 macrophages whereby high levels of NO● suppressed ferroptosis via inhibition of hydroperoxy-eicosatetraenoyl-phosphatidylethanolamine (HpETE-PE) production by 15-lipoxygenase (15LOX) complexed with PE-binding protein 1 (PEBP1). However, the mechanism of NO● interference with 15LOX/PEBP1 activity remained unclear. Here, we use a biochemical model of recombinant 15LOX-2 complexed with PEBP1, LC-MS redox lipidomics, and structure-based modeling and simulations to uncover the mechanism through which NO● suppresses ETE-PE oxidation. Our study reveals that O2 and NO● use the same entry pores and channels connecting to 15LOX-2 catalytic site, resulting in a competition for the catalytic site. We identified residues that direct O2 and NO● to the catalytic site, as well as those stabilizing the esterified ETE-PE phospholipid tail. The functional significance of these residues is supported by in silico saturation mutagenesis. We detected nitrosylated PE species in a biochemical system consisting of 15LOX-2/PEBP1 and NO● donor and in RAW264.7 M2 macrophages treated with ferroptosis-inducer RSL3 in the presence of NO●, in further support of the ability of NO● to diffuse to, and react at, the 15LOX-2 catalytic site. The results provide first insights into the molecular mechanism of repression of the ferroptotic Hp-ETE-PE production by NO●.

scholarly journals SYNTHESIS, IN SILICO CHARACTERIZATION AND EX VIVO EVALUATION OF THE NOVEL ORGANIC NITRATE NDIBP AS A POTENTIAL VASORELAXANT AGENT

2021 ◽  
pp. 124-134
Author(s):  
AIRLLA LAANA DE MEDEIROS CAVALCANTI ◽  
PATRÍCIA KEYTTH LINS ROCHA ◽  
ISADORA SILVA LUNA ◽  
MARIA CLÁUDIA RODRIGUES BRANDÃO ◽  
EMMELY OLIVEIRA DA TRINDADE ◽  
...  
Keyword(s):  
In Silico ◽  
Ex Vivo ◽  
Biological Activities ◽  
Mesenteric Arteries ◽  
Organic Nitrate ◽  
No Donor ◽  
13C Nuclear Magnetic Resonance ◽  
Activity Spectrum ◽  
Biological Activity Spectrum ◽  
In Silico Characterization

Objective: This study aimed to describe the synthesis and biological/pharmacokinetic potential of the 1,3-diisobutoxypropan-2-yl nitrate (NDIBP) using in silico and ex vivo approaches. Methods: The compound was characterized by Fourier-transform infrared spectroscopy and 1H and 13C- nuclear magnetic resonance spectra. NDIBP biological activity spectrum was obtained by Prediction of Activity Spectra for Substances (PASS). The pharmacological effect was validated in ex vivo studies using mesenteric artery. Drug-like properties and Absorption Distribution Metabolism Excretion and Toxicity (ADMET) studies were carried out by pkCSM (Predicting Small-Molecule Pharmacokinetic Properties Using Graph-Based Signatures) software. Results: PASS prediction indicated NDIBP as nitric oxide (NO) donor with vasodilator effect. Ex vivo studies validated PASS analysis and showed the NDIBP vasorelaxant activity in mesenteric arteries. Physicochemical parameters and ADMET prediction suggested that NDIBP is a drug-like molecule with a good theoretical oral bioavailability, good absorption in the gastrointestinal tract, and a low distribution in the tissues. Conclusion: All the data indicated that NDIBP possesses biological activities and drug-like properties to be considered as a vasorelaxant agent and a good candidate for further investigation in the treatment of arterial hypertension and drug development studies.

scholarly journals In silico Approach to Identify Potent Bioactive Compounds as Inhibitors against the Enoyl-acyl Carrier Protein (acp) Reductase Enzyme of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (5) ◽  
pp. 7023-7039
Keyword(s):  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Bioactive Compounds ◽  
In Silico ◽  
Acyl Carrier Protein ◽  
Cell Wall Protein ◽  
Carrier Protein ◽  
Protein Inhibitor ◽  
Mycobacterial Cell Wall ◽  
Docking Energy

The enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis elongates acyl fatty acids, which are progenitors of mycolic acids and that are mycobacterial cell wall parts. The aim is to discover potent therapeutic novel bioactive compounds as enoyl-acyl carrier protein (ACP) reductase (InhA, PDB ID: 4U0J) antagonists using an in silico drug design scheme. Structure-based computerized prediction of drug-receptor interactions. PyRx virtual screening tool was used to conduct molecular docking investigations on enoyl-ACP reductase. A target-based ligand selection strategy to choose ligand compounds was employed. The ligand structure was chosen using LEA3D-CNRS. Medication data set that was approved by the FDA: 2028 molecule (s) were used in the study. Around 27 bioactive molecules can bind to the 4U0J, with docking scores ranging from -6.2 to -11.2 Kcal/mol. Compound CHEMBL441373 was shown to have the highest acceptable docking energy (-11.1Kcal/mol), making it a good candidate for a cell wall protein inhibitor (4U0J) that should be investigated further in vivo and in vitro. The anti-mycobacterial ability of triazole scaffolding in a new therapeutic was determined. Compound CHEMBL441373 is located to possess high docking energy (-11.1Kcal/mol) and is shown as a suitable molecule of cell wall protein inhibitor (4U0J).

A systematic review with in silico analysis on transcriptomic profile of gallbladder carcinoma

2020 ◽  
Vol 47 (6) ◽  
pp. 398-408
Author(s):  
Sonam Tulsyan ◽  
Showket Hussain ◽  
Balraj Mittal ◽  
Sundeep Singh Saluja ◽  
Pranay Tanwar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Gallbladder Carcinoma ◽  
In Silico ◽  
In Silico Analysis ◽  
Transcriptomic Profile ◽  
Silico Analysis

Common and well-documented Allele List: unverzichtbares Hilfsmittel für die moderne HLA-Typisierung

2019 ◽  
Vol 9 (04) ◽  
pp. 241-245
Author(s):  
Nils Lachmann ◽  
Diana Stauch ◽  
Axel Pruß
Keyword(s):  
In Silico ◽  
Regionale Unterschiede

ZusammenfassungDie Typisierung der humanen Leukozytenantigene (HLA) vor Organ- und hämatopoetischer Stammzelltransplantation zur Beurteilung der Kompatibilität von Spender und Empfänger wird heutzutage in der Regel molekulargenetisch mittels Amplifikation, Hybridisierung oder Sequenzierung durchgeführt. Durch die exponentiell steigende Anzahl an neu entdeckten HLA-Allelen treten vermehrt Mehrdeutigkeiten, sogenannte Ambiguitäten, in der HLA-Typisierung auf, die aufgelöst werden müssen, um zu einem eindeutigen Ergebnis zu gelangen. Mithilfe kategorisierter Allelfrequenzen (häufig, gut dokumentiert und selten) in Form von CWD-Allellisten (CWD: common and well-documented) ist die In-silico-Auflösung von Ambiguitäten durch den Ausschluss seltener Allele als mögliches Ergebnis realisierbar. Ausgehend von einer amerikanischen CWD-Liste existieren derzeit auch eine europäische, deutsche und chinesische CWD-Liste, die jeweils regionale Unterschiede in den Allelfrequenzen erkennbar werden lassen. Durch die Anwendung von CWD-Allelfiltern in der klinischen HLA-Typisierung können Zeit, Kosten und Arbeitskraft eingespart werden.

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