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      Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening

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          Abstract

          The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual ‘hits’. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

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          A graphical user interface to the CCP4 program suite.

          CCP4i is a graphical user interface that makes running programs from the CCP4 suite simpler and quicker. It is particularly directed at inexperienced users and tightly linked to introductory and scientific documentation. It also provides a simple project-management system and visualization tools. The system is readily extensible and not specific to CCP4 software.
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            Rational design of potent sialidase-based inhibitors of influenza virus replication.

            Two potent inhibitors based on the crystal structure of influenza virus sialidase have been designed. These compounds are effective inhibitors not only of the enzyme, but also of the virus in cell culture and in animal models. The results provide an example of the power of rational, computer-assisted drug design, as well as indicating significant progress in the development of a new therapeutic or prophylactic treatment for influenza infection.
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              Hemoglobin metabolism in the malaria parasite Plasmodium falciparum.

              Hemoglobin degradation in intraerythrocytic malaria parasites is a vast process that occurs in an acidic digestive vacuole. Proteases that participate in this catabolic pathway have been defined. Studies of protease biosynthesis have revealed unusual targeting and activation mechanisms. Oxygen radicals and heme are released during proteolysis and must be detoxified by dismutation and polymerization, respectively. The quinoline antimalarials appear to act by preventing sequestration of this toxic heme. Understanding the disposition of hemoglobin has allowed identification of essential processes and metabolic weakpoints that can be exploited to combat this scourge of mankind.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                25 September 2015
                2015
                : 10
                : 9
                : e0138957
                Affiliations
                [1 ]Dipartimento di Scienze biochimiche "A. Rossi Fanelli", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy
                [2 ]Department of Microbiology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia
                [3 ]Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, Victoria, 3800, Australia
                [4 ]Dipartimento di Biologia e Biotecnologie "Charles Darwin", Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185, Roma, Italy
                Tulane University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: SM AP ND CR. Performed the experiments: CR ND KKS RB SM AP. Analyzed the data: CR ND SM AP. Contributed reagents/materials/analysis tools: SM AP. Wrote the paper: CR AP SM ND.

                Article
                PONE-D-15-31047
                10.1371/journal.pone.0138957
                4583420
                26406322
                908cdf02-2afc-4c5e-ba84-0715178703c1
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 15 July 2015
                : 4 September 2015
                Page count
                Figures: 6, Tables: 1, Pages: 16
                Funding
                SM acknowledges Future Fellowship support from the Australian Research Council (Grant FT100100690). CR was an Australia Endeavour Research Fellowship recipient (Grant 4100-2014). AP acknowledges Sapienza University of Rome (Grant C26A149EC4) for funding. This work was supported by the National Health and Medical Research (Grant 1063786). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All PDB files are available from the PDB database (accession number(s) 4ZQT, 5CBM). All other relevant data are within the paper and its Supporting Information files.

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