Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition

Background: DAB389IL-2 (Denileukin diftitox) as an immunotoxin is a targeted pharmaceutical protein and is the first immunotoxin approved by FDA. It is used for the treatment of various kinds of cancer such as CTCL lymphoma, melanoma, and Leukemia but among all of these, treatment of CTCL has special importance. DAB389IL-2 consists of two distinct parts; the catalytic domain of Diphtheria Toxin (DT) that genetically fused to the whole IL-2. Deamidation is the most important reaction for chemical instability of proteins occurs during manufacture and storage. Deamidation of asparagine residues occurs at a higher rate than glutamine residues. The structure of proteins, temperature and pH are the most important factors that influence the rate of deamidation. Methods: Since there is not any information about deamidation of DAB389IL-2, we studied in silico deamidation by Molecular Dynamic (MD) simulations using GROMACS software. The 3D model of fusion protein DAB389IL-2 was used as a template for deamidation. Then, the stability of deamidated and native form of the drug was calculated. Results: The results of MD simulations were showed that the deamidated form of DAB389IL-2 is more unstable than the normal form. Also, deamidation was carried by incubating DAB389IL-2, 0.3 mg/ml in ammonium hydrogen carbonate for 24 h at 37o C in order to in vitro experiment. Conclusion: The results of in vitro experiment were confirmed outcomes of in silico study. In silico and in vitro experiments were demonstrated that DAB389IL-2 is unstable in deamidated form.

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Virtual Screening, Molecular docking and in-silico ADME-Tox analysis for identification of potential main protease (Mpro) enzyme inhibitors

Anti-Infective Agents ◽

10.2174/2211352518999201208201854 ◽

2020 ◽

Vol 18 ◽

Author(s):

Debadash Panigrahi ◽

Ganesh Prasad Mishra

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

In Silico ◽

Data Bank ◽

Future Research ◽

Reference Compound ◽

Unexpected Death ◽

Main Protease ◽

In Silico Admet

Objective:: Recent pandemic caused by SARS-CoV-2 described in Wuhan China in December-2019 spread widely almost all the countries of the world. Corona virus (COVID-19) is causing the unexpected death of many peoples and severe economic loss in several countries. Virtual screening based on molecular docking, drug-likeness prediction, and in silico ADMET study has become an effective tool for the identification of small molecules as novel antiviral drugs to treat diseases. Methods:: In the current study, virtual screening was performed through molecular docking for identifying potent inhibitors against Mpro enzyme from the ZINC library for the possible treatment of COVID-19 pandemic. Interestingly, some compounds are identified as possible anti-covid-19 agents for future research. 350 compounds were screened based on their similarity score with reference compound X77 from ZINC data bank and were subjected to docking with crystal structure available of Mpro enzyme. These compounds were then filtered by their in silico ADME-Tox and drug-likeness prediction values. Result:: Out of these 350 screened compounds, 10 compounds were selected based on their docking score and best docked pose in comparison to the reference compound X77. In silico ADME-Tox and drug likeliness predictions of the top compounds were performed and found to be excellent results. All the 10 screened compounds showed significant binding pose with the target enzyme main protease (Mpro) enzyme and satisfactory pharmacokinetic and toxicological properties. Conclusion:: Based on results we can suggest that the identified compounds may be considered for therapeutic development against the COVID-19 virus and can be further evaluated for in vitro activity, preclinical, clinical studies and formulated in a suitable dosage form to maximize their bioavailability.

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A small molecule compound with an indole moiety inhibits the main protease of SARS-CoV-2 and blocks virus replication

Nature Communications ◽

10.1038/s41467-021-20900-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shin-ichiro Hattori ◽

Nobuyo Higashi-Kuwata ◽

Hironori Hayashi ◽

Srinivasa Rao Allu ◽

Jakka Raghavaiah ◽

...

Keyword(s):

Small Molecule ◽

Covalent Bond ◽

Amino Acid Residues ◽

X Ray ◽

Viral Breakthrough ◽

Main Protease ◽

Small Molecule Compound ◽

Polar Interactions ◽

High Concentrations

AbstractExcept remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline and indole moiety, respectively, which target the SARS-CoV-2 main protease (Mpro). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, and immunocytochemistry and show both compounds to block the infectivity of SARS-CoV-2 with EC50 values of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. Remdesivir permitted viral breakthrough at high concentrations; however, compound 5h completely blocks SARS-CoV-2 infection in vitro without viral breakthrough or detectable cytotoxicity. Combination of 5h and remdesivir exhibits synergism against SARS-CoV-2. Additional X-ray structural analysis show that 5h forms a covalent bond with Mpro and makes polar interactions with multiple active site amino acid residues. The present data suggest that 5h might serve as a lead Mpro inhibitor for the development of therapeutics for SARS-CoV-2 infection.

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Effect of hydrophobically modified PEO polymers (PEO-dodecyl) on oil/water microemulsion properties: in vitro and in silico investigations

RSC Advances ◽

10.1039/d0ra09804c ◽

2021 ◽

Vol 11 (12) ◽

pp. 7059-7069

Author(s):

M. Khatouri ◽

R. Ahfir ◽

M. Lemaalam ◽

S. El Khaoui ◽

A. Derouiche ◽

...

Keyword(s):

Integral Equations ◽

In Silico ◽

Md Simulations ◽

Hydrophobically Modified ◽

Oil Water

In this work, we study the effect of grafted PEO-dodecyl co-polymers on the decane/water microemulsions properties. For this purpose, we combined the MD simulations, the OZ integral equations resolved using the HNC closure, and SANS experiments.

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ERRATUM: "In silico modeling and in vitro activity of vitexin and isovitexin against SGLT2"

Journal of Theoretical and Computational Chemistry ◽

10.1142/s0219633620920017 ◽

2020 ◽

Vol 19 (05) ◽

pp. 2092001

Author(s):

Yongheng Shi ◽

Fancui Meng ◽

Jiping Liu ◽

Bin Wang

Keyword(s):

In Silico ◽

Vitro Activity ◽

In Vitro Activity ◽

In Silico Modeling

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Designing new antimalarial hits from African medicinal plants at the University of Buea (Cameroon); Part I: Isolation, in vitro activity, in silico “drug-likeness” and Pharmacokinetic profiles

International Journal of Infectious Diseases ◽

10.1016/j.ijid.2016.02.324 ◽

2016 ◽

Vol 45 ◽

pp. 131

Author(s):

D. Zofou

Keyword(s):

Medicinal Plants ◽

In Silico ◽

Vitro Activity ◽

In Vitro Activity ◽

Pharmacokinetic Profiles ◽

The University

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In silico screening of phytoconstituents with antiviral activities against SARS-COV-2 main protease, Nsp12 polymerase and Nsp13 helicase proteins

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210317162502 ◽

2021 ◽

Vol 18 ◽

Author(s):

Jainey James ◽

Divya Jyothi ◽

Sneh Priya

Keyword(s):

Antiviral Activity ◽

Molecular Interactions ◽

In Silico ◽

Antiviral Treatment ◽

In Vivo Studies ◽

Main Protease ◽

Hypothesis Model ◽

Antiviral Activities ◽

Pharmacophore Hypothesis

Aims: The present study aim was to analyse the molecular interactions of the phytoconstituents known for their antiviral activity with the SARS-CoV-2 nonstructural proteins such as main protease (6LU7), Nsp12 polymerase (6M71), and Nsp13 helicase (6JYT). The applied in silico methodologies was molecular docking and pharmacophore modeling using Schrodinger software. Methods: The phytoconstituents were taken from PubChem, and SARS-CoV-2 proteins were downloaded from the protein data bank. The molecular interactions, binding energy, ADMET properties and pharmacophoric features were analysed by glide XP, prime MM-GBSA, qikprop and phase application of Schrodinger respectively. The antiviral activity of the selected phytoconstituents was carried out by PASS predictor, online tools. Results: The docking score analysis showed that quercetin 3-rhamnoside (-8.77 kcal/mol) and quercetin 3-rhamnoside (-7.89 kcal/mol) as excellent products to bind with their respective targets such as 6LU7, 6M71 and 6JYT. The generated pharmacophore hypothesis model validated the docking results, confirming the hydrogen bonding interactions of the amino acids. The PASS online tool predicted constituent's antiviral potentials. Conclusion: The docked phytoconstituents showed excellent interactions with the SARS-CoV-2 proteins, and on the outset, quercetin 3-rhamnoside and quercetin 7-rhamnoside have well-interacted with all the three proteins, and these belong to the plant Houttuynia cordata. The pharmacophore hypothesis has revealed the characteristic features responsible for their interactions, and PASS prediction data has supported their antiviral activities. Thus, these natural compounds could be developed as lead molecules for antiviral treatment against SARS-CoV-2. Further in-vitro and in-vivo studies could be carried out to provide better drug therapy.

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