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      The structural model of Zika virus RNA-dependent RNA polymerase in complex with RNA for rational design of novel nucleotide inhibitors

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          Abstract

          Zika virus is a global health threat due to significantly elevated risk of fetus malformations in infected pregnant women. Currently, neither an effective therapy nor a prophylactic vaccination is available for clinical use, desperately necessitating novel therapeutics and approaches to obtain them. Here, we present a structural model of the Zika virus RNA-dependent RNA polymerase (ZIKV RdRp) in complex with template and nascent RNAs, Mg 2+ ions and accessing nucleoside triphosphate. The model allowed for docking studies aimed at effective pre-screening of potential inhibitors of ZIKV RdRp. Applicability of the structural model for docking studies was illustrated with the NITD008 artificial nucleotide that is known to effectively inhibit the function of the ZIKV RdRp. The ZIKV RdRp – RNA structural model is provided for all possible variations of the nascent RNA bases pairs to enhance its general utility in docking and modelling experiments. The developed model makes the rational design of novel nucleosides and nucleotide analogues feasible and thus provides a solid platform for the development of advanced antiviral therapy.

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            Ab initio effective core potentials for molecular calculations. Potentials for main group elements Na to Bi

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              Very fast empirical prediction and rationalization of protein pKa values.

              A very fast empirical method is presented for structure-based protein pKa prediction and rationalization. The desolvation effects and intra-protein interactions, which cause variations in pKa values of protein ionizable groups, are empirically related to the positions and chemical nature of the groups proximate to the pKa sites. A computer program is written to automatically predict pKa values based on these empirical relationships within a couple of seconds. Unusual pKa values at buried active sites, which are among the most interesting protein pKa values, are predicted very well with the empirical method. A test on 233 carboxyl, 12 cysteine, 45 histidine, and 24 lysine pKa values in various proteins shows a root-mean-square deviation (RMSD) of 0.89 from experimental values. Removal of the 29 pKa values that are upper or lower limits results in an RMSD = 0.79 for the remaining 285 pKa values. Proteins 2005. 2005 Wiley-Liss, Inc.
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                Author and article information

                Contributors
                boura@uochb.cas.cz
                nencka@uochb.cas.cz
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 July 2018
                24 July 2018
                2018
                : 8
                : 11132
                Affiliations
                [1 ]ISNI 0000 0001 2188 4245, GRID grid.418892.e, Gilead Sciences Research Centre at IOCB Prague, , Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, ; Praha, Czech Republic
                [2 ]ISNI 0000 0001 2188 4245, GRID grid.418892.e, Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, ; Praha, Czech Republic
                [3 ]ISNI 0000 0001 2285 286X, GRID grid.426567.4, Veterinary Research Institute, ; Hudcova 70, CZ-62100 Brno, Czech Republic
                [4 ]Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005 Ceske Budejovice, Czech Republic
                Article
                29459
                10.1038/s41598-018-29459-7
                6057956
                30042483
                29319519-eab4-4a9f-b1e1-3f62ee400880
                © The Author(s) 2018

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 April 2018
                : 9 July 2018
                Funding
                Funded by: Academy of Sciences Czech Republic (RVO: 61388963)
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