The Screening of phytochemicals against NS5 Polymerase to treat Zika Virus infection: Integrated computational based approach

Background: The recent Zika virus (ZIKV) outbreak provides a spur for new, efficient, and safe anti-Zika Virus agents. RNA-dependent RNA polymerase (RdRp) is critical amongst the seven non-structural proteins for viral replication and is considered an attractive drug target. Methods: In this study, a molecular docking approach was used to rationally screen the library of 5000 phytochemicals to find inhibitors against NS5 RdRp. LigX tool was used to analyze the 2D plots of receptor-ligand interactions. The top-ranked compounds were then subjected to in-silico pharmacokinetic study. Results: The compounds, namely Polydatin, Dihydrogenistin, Liquiritin, Rhapontin, and Cichoriin, successfully bind inside the pocket of NS5 RdRp. Polydatin was the leading phytochemical that showed high docking score of -18.71 (kcal/mol) and bonding interaction at the active site of NS5 RdRp. They were subjected to analysis for drug-like properties that further reinforced their validation and showed that they could attach with the receptor more than SOFOSBUVIR control drugs. MD simulation of the top two complexes was performed, and the simulated complexes showed stability, and ligands were kept within the bonding pocket. Conclusion: The study might facilitate the development of a natural and cost-effective drug against ZIKV. Further validation, however, is necessary to confirm its drug effectiveness and its biocompatibility.

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The analysis of NQO1 isoforms as an Off-target to anti-cancer drug RH1 using molecular modeling and structure-based drug discovery approaches

International Journal of Research in Pharmaceutical Sciences ◽

10.26452/ijrps.v11i3.2550 ◽

2020 ◽

Vol 11 (3) ◽

pp. 3780-3792

Author(s):

Pramodkumar P Gupta ◽

Shanker L Kothari ◽

Mindaugas Valius ◽

Jonas Cicenas ◽

Virupaksha A Bastikar

Keyword(s):

Drug Target ◽

Conformational Stability ◽

3D Structure ◽

Protein Isoforms ◽

Cancer Drug ◽

Normal Tissues ◽

Protein Ligand Interactions ◽

Ligand Interactions ◽

Docking Approach ◽

High Level

NQO1 is already evaluated for its high-level expression in numerous human cancers as compared with normal tissues. RH1 acts as an indigenous prodrug to NQO1. In our preceding work Off-targeting of (RH1) drug to protein kinases is well reported. Numerous protein isoforms have reported a potential drug target and biomarkers in cancer and related diseases. In the present study, the 3D structure of all the three NQO1 isoforms is modelled using the homologybased concept, evaluated for their conformational stability and energy forms by MD simulation. MSA and related method used for binding site prediction. Protein-ligand interactions were studied using molecular docking approach. The 3D modelled structure of NQO1 isoform 2 and 3 exhibited a conformational change in the protein FAD and RH1 binding region due to the absence of a few key amino acids. Docking results revealed a good degree of binding energy and interaction between the selected NQO1 isoforms, FAD and RH1. As FAD acts as a floor surface to RH1, a similar trend observed in the NQO1 isoform 2 and 3. Hence the NQO1 isoforms 2 and 3 could be a drug target to anticancer prodrug RH1 and can be further investigated in the lab.

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Combining Docking and Molecular Dynamic of Protease from Bacillus lehensis G1

Journal of Engineering and Science Research ◽

10.26666/rmp.jesr.2018.1.1 ◽

2018 ◽

Vol 2 (1) ◽

pp. 1-5

Author(s):

Noorul Aini Sulaiman ◽

Keyword(s):

Molecular Docking ◽

Molecular Dynamic ◽

Md Simulation ◽

Enzyme Stability ◽

3D Structure ◽

Cost Effective ◽

Hydrophobic Region ◽

Enzyme Substrate ◽

Docking Approach ◽

The Stability

Protease is an enzyme that catalysed the hydrolysis of protein into peptide. Application of protease in industry has been linked with cost effective substrates and complex of enzyme-substrate stability. Molecular docking approach has identified casein as a preference substrates. However, lack of data on casein mode of binding to protease and enzyme stability represents a limitation for its production and structural optimization. In this study, we have used a molecular dynamic (MD) to examine the stability of complex enzyme-substrate of protease from Bacillus lehensis G1. The 3D structure of protease (BleG1_1979) was docked with substrate casein using AutoDock Vina. Structural analysis of the substrate-binding cleft revealed a binding site of casein was predominantly at the hydrophobic region of BleG1_1979. The MD of complex BleG1_1979-casein was tested with two temperatures; 298 K and 310 K using GROMACS v5.1.4. MD simulation showed a stable behaviour of BleG1_1979 over the 20 ns simulation period. The molecular docking and MD simulation suggested that the production of protease from B. lehensis G1 by utilization of casein and the stability of complex protease-casein could be a potential application to generate a cost effective enzyme to be develop for industrial use.

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Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01967-16 ◽

2016 ◽

Vol 61 (3) ◽

Cited By ~ 24

Author(s):

Gaofei Lu ◽

Gregory R. Bluemling ◽

Paul Collop ◽

Michael Hager ◽

Damien Kuiper ◽

...

Keyword(s):

Rna Polymerase ◽

Zika Virus ◽

Nonstructural Protein ◽

Rna Dependent Rna Polymerase ◽

Antiviral Compounds ◽

Double Stranded Dna ◽

Virus Rna ◽

Potential Inhibitors

ABSTRACT Zika virus (ZIKV) is an emerging human pathogen that is spreading rapidly through the Americas and has been linked to the development of microcephaly and to a dramatically increased number of Guillain-Barré syndrome cases. Currently, no vaccine or therapeutic options for the prevention or treatment of ZIKV infections exist. In the study described in this report, we expressed, purified, and characterized full-length nonstructural protein 5 (NS5) and the NS5 polymerase domain (NS5pol) of ZIKV RNA-dependent RNA polymerase. Using purified NS5, we developed an in vitro nonradioactive primer extension assay employing a fluorescently labeled primer-template pair. Both purified NS5 and NS5pol can carry out in vitro RNA-dependent RNA synthesis in this assay. Our results show that Mn2+ is required for enzymatic activity, while Mg2+ is not. We found that ZIKV NS5 can utilize single-stranded DNA but not double-stranded DNA as a template or a primer to synthesize RNA. The assay was used to compare the efficiency of incorporation of analog 5′-triphosphates by the ZIKV polymerase and to calculate their discrimination versus that of natural ribonucleotide triphosphates (rNTPs). The 50% inhibitory concentrations for analog rNTPs were determined in an alternative nonradioactive coupled-enzyme assay. We determined that, in general, 2′-C-methyl- and 2′-C-ethynyl-substituted analog 5′-triphosphates were efficiently incorporated by the ZIKV polymerase and were also efficient chain terminators. Derivatives of these molecules may serve as potential antiviral compounds to be developed to combat ZIKV infection. This report provides the first characterization of ZIKV polymerase and demonstrates the utility of in vitro polymerase assays in the identification of potential ZIKV inhibitors.

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Prediction of Anti-COVID 19 Therapeutic Power of Medicinal Moroccan Plants Using Molecular Docking

Bioinformatics and Biology Insights ◽

10.1177/11779322211009199 ◽

2021 ◽

Vol 15 ◽

pp. 117793222110091

Author(s):

Badreddine Nouadi ◽

Abdelkarim Ezaouine ◽

Mariame El Messal ◽

Mohamed Blaghen ◽

Faiza Bennis ◽

...

Keyword(s):

Molecular Docking ◽

Medicinal Plants ◽

Drug Target ◽

Cost Effective ◽

Current Medical Research ◽

New Drugs ◽

Binding Affinities ◽

Global Public Health ◽

Public Health Challenge ◽

Ucsf Chimera

The emerging pathogen SARS-CoV2 causing coronavirus disease 2019 (COVID-19) is a global public health challenge. To the present day, COVID-19 had affected more than 40 million people worldwide. The exploration and the development of new bioactive compounds with cost-effective and specific anti-COVID 19 therapeutic power is the prime focus of the current medical research. Thus, the exploitation of the molecular docking technique has become essential in the discovery and development of new drugs, to better understand drug-target interactions in their original environment. This work consists of studying the binding affinity and the type of interactions, through molecular docking, between 54 compounds from Moroccan medicinal plants, dextran sulfate and heparin (compounds not derived from medicinal plants), and 3CLpro-SARS-CoV-2, ACE2, and the post fusion core of 2019-nCoV S2 subunit. The PDB files of the target proteins and prepared herbal compounds (ligands) were subjected for docking to AutoDock Vina using UCSF Chimera, which provides a list of potential complexes based on the criteria of form complementarity of the natural compound with their binding affinities. The results of molecular docking revealed that Taxol, Rutin, Genkwanine, and Luteolin-glucoside have a high affinity with ACE2 and 3CLpro. Therefore, these natural compounds can have 2 effects at once, inhibiting 3CLpro and preventing recognition between the virus and ACE2. These compounds may have a potential therapeutic effect against SARS-CoV2, and therefore natural anti-COVID-19 compounds.

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