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      Structural insights into inhibition of PRRSV Nsp4 revealed by structure-based virtual screening, molecular dynamics, and MM-PBSA studies

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          Abstract

          Background

          Porcine reproductive and respiratory syndrome respiratory sickness in weaned and growing pigs, as well as sow reproductive failure, and its infection is regarded as one of the most serious swine illnesses worldwide. Given the current lack of an effective treatment, in this study, we identified natural compounds capable of inhibiting non-structural protein 4 (Nsp4) of the virus, which is involved in their replication and pathogenesis.

          Results

          We screened natural compounds ( n = 97,999) obtained from the ZINC database against Nsp4 and selected the top 10 compounds for analysing protein–ligand interactions and physicochemical properties. The five compounds demonstrating strong binding affinity were then subjected to molecular dynamics simulations (100 ns) and binding free energy calculations. Based on analysis, we identified four possible lead compounds that represent potentially effective drug-like inhibitors.

          Conclusions

          These methods identified that these natural compounds are capable of inhibiting Nsp4 and possibly effective as antiviral therapeutics against PRRSV.

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          Most cited references56

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          UCSF Chimera--a visualization system for exploratory research and analysis.

          The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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            AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.

            AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user. Copyright 2009 Wiley Periodicals, Inc.
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              The Protein Data Bank.

              The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.
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                Author and article information

                Contributors
                junmokim@cau.ac.kr
                Journal
                J Biol Eng
                J Biol Eng
                Journal of Biological Engineering
                BioMed Central (London )
                1754-1611
                22 February 2022
                22 February 2022
                2022
                : 16
                Affiliations
                GRID grid.254224.7, ISNI 0000 0001 0789 9563, Department of Animal Science and Technology, , Chung-Ang University, ; Anseong-si, Gyeonggi-do 17546 Republic of Korea
                Article
                284
                10.1186/s13036-022-00284-x
                8864930
                35193698
                e73eedf7-b9fd-4e73-b60c-bd87f021bf89
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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                Research
                Custom metadata
                © The Author(s) 2022

                Biotechnology
                prrsv,swine,nsp4,molecular dynamics,protein–ligand interaction
                Biotechnology
                prrsv, swine, nsp4, molecular dynamics, protein–ligand interaction

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