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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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              GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers

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                Author and article information

                Contributors
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                Journal
                Journal of Biological Engineering
                J Biol Eng
                Springer Science and Business Media LLC
                1754-1611
                December 2022
                February 22 2022
                December 2022
                : 16
                : 1
                Article
                10.1186/s13036-022-00284-x
                e73eedf7-b9fd-4e73-b60c-bd87f021bf89
                © 2022

                https://creativecommons.org/licenses/by/4.0

                https://creativecommons.org/licenses/by/4.0

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