An insight into the interaction between α-ketoamide- based inhibitor and coronavirus main protease: A detailed in silico study

In most of the pathogenic organisms including Plasmodium falciparum, isoprenoids are synthesized via MEP (MethylErythritol 4-Phosphate) pathway. LytB is the last enzyme of this pathway which catalyzes the conversion of (E)-4-hydroxy-3-methylbut-2-en-1-yl diphosphate (HMBPP) into the two isoprenoid precursors: isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Since the MEP pathway is not used by humans, it represents an attractive target for the development of new antimalarial compounds or inhibitors. Here a systematic in-silico study has been conducted to get an insight into the structure of Plasmodium lytB as well as its affinities towards different inhibitors. We used comparative modeling technique to predict the three dimensional (3D) structure of Plasmodium LytB taking E. Coli LytB protein (PDB ID: 3KE8) as template and the model was subsequently refined through molecular dynamics (MD) simulation. A large ligand dataset containing diphospate group was subjected for virtual screening against the target using GOLD 5.2 program. Considering the mode of binding and affinities, 17 leads were selected on basis of binding energies in comparison to its substrate HMBPP (Gold.Chemscore.DG: -20.9734 kcal/mol). Among them, 5 were discarded because of their inhibitory activity towards other human enzymes. The rest 12 potential leads carry all the properties of any "drug like" molecule and the knowledge of Plasmodium LytB inhibitory mechanism which can provide valuable support for the antimalarial inhibitor design in future.

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Glucose antimetabolite 2-Deoxy-D-Glucose and its derivative as promising candidates for tackling COVID-19: Insights derived from in silico docking and molecular simulations

10.22541/au.158567174.40895611/v2 ◽

2021 ◽

Author(s):

Acharya Balkrishna ◽

Pallavi Thakur ◽

Shivam Singh ◽

Swami Dev ◽

Viney Jain ◽

...

Keyword(s):

Hydrogen Bond ◽

In Silico ◽

Model Systems ◽

Respiratory Pathogen ◽

Spike Glycoprotein ◽

In Silico Docking ◽

Main Protease ◽

Viral Virulence ◽

In Silico Study ◽

Viral Receptors

A novel respiratory pathogen, SARS-CoV-2 has recently received worldwide attention and has been declared a public health emergency of global concern. Entry of SARS-CoV-2 is mediated through the viral spike glycoprotein (S2). Afterwards, the virus gets hold of the host cell machinery by employing the use of viral main protease 3CLpro and NSP15 endoribonuclease. In the present in silico study, active site mapping of the viral virulence factors was rendered by means of DoG Site Scorer. The possibility of repurposing of 2-deoxy-D-glucose (2-DG), a radio-chemo-modifier drug used for optimizing cancer therapy, and one of its derivative (1, 3, 4, 6-Tetra-O-acetyl-2-deoxy-D-glucopyranose, has been investigated by conducting ligand-receptor docking. Binding pose depictions of ligands and viral receptors were assessed by employing molecular dynamics analysis. Molinspiration and Toxicity Estimation Software tools were used to assess the drug likeliness, bioactivity indices and ADMETox values. 2-DG can dock efficiently with viral main protease 3CLpro as well as NSP15 endoribonuclease, thus efficiently inactivating these viral receptors leading to incapacitation of the SARS-CoV-2 virus. Such incapacitation was possible by means of formation of a hydrogen bond between 2-DG and proline residues of viral protease. The 2-DG derivative formed a hydrogen bond with the glutamine amino acid residues of the viral spike glycoprotein. The present in silico study supports the potential benefits of using 2-DG and its glucopyranose derivative as repurposed drugs/prodrugs for mitigating the novel COVID-19 infection. Since both these moieties present no signs of serious toxicity, further empirical studies on model systems and human clinical trials to ascertain effective dose-response are warranted and should be urgently initiated.

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Chlorogenic acid may be a potent inhibitor of dimeric SARS-CoV-2 main protease 3CLpro: an in silico study

Traditional Medicine Research ◽

10.53388/tmr20201208211 ◽

2021 ◽

Vol 6 (2) ◽

pp. 20

Author(s):

Rajkumar Sanjay ◽

Vishal Shivalingappa ◽

Nayeem A. ◽

Shailendra Sanjay

Keyword(s):

Chlorogenic Acid ◽

In Silico ◽

Potent Inhibitor ◽

Main Protease ◽

In Silico Study

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Potent Inhibitors for SARS-COV-2 Main Protease: An in-Silico Study for Drug Development

10.22541/au.160283350.06650646/v1 ◽

2020 ◽

Author(s):

Ibrahim Khater ◽

Aaya Nassar

Keyword(s):

Drug Development ◽

In Silico ◽

Main Protease ◽

In Silico Study

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Reprofiling of approved drugs against SARS-CoV-2 main protease: an in-silico study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1845976 ◽

2020 ◽

pp. 1-15

Author(s):

Prateek Kumar ◽

Taniya Bhardwaj ◽

Ankur Kumar ◽

Bhuvaneshwari R. Gehi ◽

Shivani K. Kapuganti ◽

...

Keyword(s):

In Silico ◽

Main Protease ◽

In Silico Study ◽

Approved Drugs

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Insight into potential toxicity mechanisms of melamine: An in silico study

Toxicology ◽

10.1016/j.tox.2011.02.009 ◽

2011 ◽

Vol 283 (2-3) ◽

pp. 96-100 ◽

Cited By ~ 26

Author(s):

Chao Ma ◽

Hong Kang ◽

Qi Liu ◽

Ruixin Zhu ◽

Zhiwei Cao

Keyword(s):

In Silico ◽

Potential Toxicity ◽

In Silico Study ◽

Toxicity Mechanisms ◽

Insight Into

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Computational Studies Towards Identification of Lead Herbal Compounds of Medicinal Importance for Development of Nutraceutical Against COVID-19

10.26434/chemrxiv.12581819 ◽

2020 ◽

Author(s):

Amit Kumar Srivastav ◽

Sanjeev Kumar Gupta ◽

Umesh Kumar

Keyword(s):

Molecular Docking ◽

In Silico ◽

Md Simulation ◽

Low Cost ◽

Computational Studies ◽

Ramachandran Plot ◽

Lead Compounds ◽

Cryo Electron Microscopy ◽

Main Protease ◽

In Silico Study

In the present study, we have performed the in-silico study of SARS-CoV-2 structure with different herbal compounds of medicinal importance. We selected four <a>viral key proteins of SARS-CoV-2 </a>structure i.e ACE-2 Receptor, Main Protease (Mpro), APO Form, Cryo- electron microscopy structure for the Molecular docking followed by the molecular dynamic simulation. Using this simple in silico approach based on the molecular docking and <a>MD simulation </a>of protein and phytochemicals, we have identified potential lead candidates for the development of low cost nutraceuticals, which can be used against SARS-CoV-2 virus. Our analysis suggested that phytochemicals obtained from <i>Phyllanthus emblica</i> and <i>Azadirachta indica</i> have the highest potential to bind with ACE2 receptor or main protease of SARS-CoV-2, inhibiting the protease enzymatic activity. The lead compounds of herbal origin were docked and simulated on viral key proteins of SARS-CoV-2 structure to evaluate the binding affinity of these phytochemicals along with the type of interaction and its stability in terms of <a>RMSD</a> and <a>Ramachandran plot</a>. Further, these results were also verified by drug likeness properties by using SwissADME software. Overall, our results suggest that out of 14 herbal compounds, Nimbolide and Withaferin-A has great potential to be developed as low-cost nutraceuticals against SARS-CoV-2 virus, which is the need of hour.

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