Molecular docking and high throughput screening of designed potent inhibitor to PTPN11 involved in Peptic Ulcer

In the current study we carried out computational drug designing and dock-ing studies on Tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Scaffold selection was based on the functional properties of PTPN11. Leads were identified based on several physiochemical properties and we created our library with those new molecules that were generated based on Lipinski's rule of five. Further, we carried out high throughput screening on 21 molecules from scaffolds selected. Screening of molecules was based on the criterions such as, TOPKAT (toxicity analysis) and ADMET (absorption, distribution, metabolism, elimination) properties. Among the ligands de-signed, only one compound was identified to have premium interaction within the targeted domain. Pharmacophore was generated and analyzed for selected drug candidate. Our results suggest that O-(3-hydroxy-4-methoxyphenyl) S-methyl dithio dicarbonate is a potent drug molecule in terms of physiochemical and docking properties. In conclusion, the identified compound has great potential to inhibit tyrosine-protein phosphatase non-receptor type 11 (PTPN11).

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Identification of Anti-malarial Drug Candidate Inhibitors using Ultra-high Throughput Screening Methods and Subsequent Mechanism of Action Studies Aimed at the Treatment and Prevention of Plasmodium falciparum

10.14264/uql.2019.548 ◽

2019 ◽

Author(s):

Timothy Patrick Spicer

Keyword(s):

Plasmodium Falciparum ◽

High Throughput ◽

Mechanism Of Action ◽

High Throughput Screening ◽

Drug Candidate ◽

Screening Methods ◽

Treatment And Prevention

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New Spiro[cycloalkane-pyridazinone] Derivatives with Favorable Fsp3 Character

Chemistry ◽

10.3390/chemistry2040055 ◽

2020 ◽

Vol 2 (4) ◽

pp. 837-848

Author(s):

Csilla Sepsey Für ◽

Hedvig Bölcskei

Keyword(s):

High Throughput Screening ◽

Pharmaceutical Companies ◽

Compound Library ◽

Aromatic Rings ◽

Lead Discovery ◽

Lipinski’S Rule ◽

Design And Synthesis ◽

Lipinski’S Rule Of Five ◽

Pyridazinone Derivatives ◽

New Compounds

The large originator pharmaceutical companies need more and more new compounds for their molecule banks, because high throughput screening (HTS) is still a widely used method to find new hits in the course of the lead discovery. In the design and synthesis of a new compound library, important points are in focus nowadays: Lipinski’s rule of five (RO5); the high Fsp3 character; the use of bioisosteric heterocycles instead of aromatic rings. With said aim in mind, we have synthesized a small compound library of new spiro[cycloalkane-pyridazinones] with 36 members. The compounds with this new scaffold may be useful in various drug discovery projects.

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Developing an in silico pipeline for faster drug candidate discovery: Virtual high throughput screening with the Signature molecular descriptor using support vector machine models

Chemical Engineering Science ◽

10.1016/j.ces.2016.02.037 ◽

2017 ◽

Vol 159 ◽

pp. 31-42 ◽

Cited By ~ 12

Author(s):

Jonathan Jun Feng Chen ◽

Donald Patrick Visco Jr.

Keyword(s):

Support Vector Machine ◽

High Throughput ◽

In Silico ◽

High Throughput Screening ◽

Molecular Descriptor ◽

Drug Candidate ◽

Support Vector

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High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/178513 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Szabolcs Gergely ◽

Csaba Hegedűs ◽

Petra Lakatos ◽

Katalin Kovács ◽

Renáta Gáspár ◽

...

Keyword(s):

Cell Death ◽

High Throughput ◽

High Throughput Screening ◽

Antitumor Agents ◽

Radical Scavenging ◽

Drug Candidate ◽

Necrotic Cell ◽

Rat Cardiomyocytes ◽

Scavenging Effect ◽

Radical Scavenging Effect

Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge’s DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury.

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Novel Coronavirus (SARS-CoV-2) Main Protease: Molecular docking of Puerarin as a Potential inhibitor

10.21203/rs.3.rs-37794/v1 ◽

2020 ◽

Author(s):

Oluwafemi Adeleke Ojo ◽

Adebola Busola Ojo ◽

Odunayo Anthonia Taiwo ◽

Olarewaju M Oluba

Keyword(s):

Molecular Docking ◽

Rna Virus ◽

Drug Candidate ◽

Lipinski’S Rule ◽

Global Pandemic ◽

Main Protease ◽

Lipinski’S Rule Of Five ◽

Novel Coronavirus ◽

Research World ◽

High Binding Affinity

Abstract SARS-CoV-2 a single stranded RNA virus which triggered the global pandemic Coronavirus Disease- 2019 (COVID-2019). It has infected about 2,844,712 patients and brought forth mortality rate to about 201,315 among 216 countries as cited by WHO. Drugs including Chloroquine and Hydroxychloroquine derivatives are being administered in most urgent cases; although, with probable side effects to people with metabolic disorders. Thus, unavailability of authorized drugs and treatment for this pandemic demands the research world to discover natural compounds with potency to cure it. This paper assesses the isoflavonoid puerarin from Pueraria lobata as a possible inhibitor of the main protease of SARS-COV-2 (Mpro) via in silico approach, for example molecular docking, Lipinski’s rule of five and toxicity prediction (ADME). Puerarin revealed high binding affinity with the target site of SARS-CoV-2 main protease. This compound slightly meets the criteria of Lipinski’s rule and does not possess properties that could cause adverse effects in humans thus, making puerarin a potential drug candidate to investigate for its usage against COVID-19.

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A simple and sensitive detection of the binding ligands by using the receptor aggregation and NMR spectroscopy: a test case of the maltose binding protein

Journal of Biomolecular NMR ◽

10.1007/s10858-021-00381-x ◽

2021 ◽

Author(s):

Young Kee Chae ◽

Yoonjin Um ◽

Hakbeom Kim

Keyword(s):

High Throughput ◽

High Throughput Screening ◽

Target Protein ◽

Test Case ◽

Ligand Interaction ◽

Drug Candidates ◽

Receptor Aggregation ◽

Simple Detection ◽

Protein Ligand Interaction ◽

Potent Drug

AbstractProtein-ligand interaction is one of the highlights of molecular recognition. The most popular application of this type of interaction is drug development which requires a high throughput screening of a ligand that binds to the target protein. Our goal was to find a binding ligand with a simple detection, and once this type of ligand was found, other methods could then be used to measure the detailed kinetic or thermodynamic parameters. We started with the idea that the ligand NMR signal would disappear if it was bound to the non-tumbling mass. In order to create the non-tumbling mass, we tried the aggregates of a target protein, which was fused to the elastin-like polypeptide. We chose the maltose binding proteinas a test case, and we tried it with several sugars, which included maltose, glucose, sucrose, lactose, galactose, maltotriose, and β-cyclodextrin. The maltose signal in the H-1 NMR spectrum disappeared completely as hoped around the protein to ligand ratio of 1:3 at 298 K where the proteins aggregated. The protein signals also disappeared upon aggregation except for the fast-moving part, which resulted in a cleaner background than the monomeric form. Since we only needed to look for a disappearing signal amongst those from the mixture, it should be useful in high throughput screening. Other types of sugars except for the maltotriose and β-cyclodextrin, which are siblings of the maltose, did not seem to bind at all. We believe that our system would be especially more effective when dealing with a smaller target protein, so both the protein and the bound ligand would lose their signals only when the aggregates formed. We hope that our proposed method would contribute to accelerating the development of the potent drug candidates by simultaneously identifying several binders directly from a mixture.

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An Ultra-High-Throughput Screen for Catalytic Inhibitors of Serine/Threonine Protein Phosphatases Types 1 and 5 (PP1C and PP5C)

SLAS DISCOVERY Advancing Life Sciences ◽

10.1177/1087057116668852 ◽

2016 ◽

Vol 22 (1) ◽

pp. 21-31 ◽

Cited By ~ 2

Author(s):

Mark Swingle ◽

Claude-Henry Volmar ◽

S. Adrian Saldanha ◽

Peter Chase ◽

Christina Eberhart ◽

...

Keyword(s):

Small Molecule ◽

High Throughput ◽

Protein Phosphatase ◽

High Throughput Screening ◽

Small Molecule Inhibitors ◽

Chemical Probes ◽

Enzymatic Assays ◽

Protein Substrates ◽

Specific Inhibitors ◽

Made In

Although there has been substantial success in the development of specific inhibitors for protein kinases, little progress has been made in the identification of specific inhibitors for their protein phosphatase counterparts. Inhibitors of PP1 and PP5 are desired as probes for research and to test their potential for drug development. We developed and miniaturized (1536-well plate format) nearly identical homogeneous, fluorescence intensity (FLINT) enzymatic assays to detect inhibitors of PP1 or PP5. The assays were used in an ultra-high-throughput screening (uHTS) campaign, testing >315,000 small-molecule compounds. Both assays demonstrated robust performance, with a Z′ of 0.92 ± 0.03 and 0.95 ± 0.01 for the PP1 and PP5 assays, respectively. Screening the same library with both assays aided the identification of class inhibitors and assay artifacts. Confirmation screening and hit prioritization assays used [32P/33P]-radiolabel protein substrates, revealing excellent agreement between the FLINT and radiolabel assays. This screening campaign led to the discovery of four novel unrelated small-molecule inhibitors of PP1 and ~30 related small-molecule inhibitors of PP5. The results suggest that this uHTS approach is suitable for identifying selective chemical probes that inhibit PP1 or PP5 activity, and it is likely that similar assays can be developed for other PPP-family phosphatases.

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