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Computer-Aided Drug Discovery from Marine Compounds: Identification of the Three-Dimensional Structural Features Responsible for Antimalarial Activity

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Blue Biotechnology

Part of the book series: Progress in Molecular and Subcellular Biology ((MMB,volume 55))

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Abstract

An integrated computational approach, based on molecular dynamics/mechanics, semi-empirical, and DFT calculations as well as dynamic docking studies, has been employed to gain insight into the mechanism of action of new antimalarial agents characterized by the scaffold of the marine compounds plakortin and aplidinone. The results of this approach show that these molecules, after interaction with Fe(II), likely coming from the heme molecule, give rise to the formation of radical species, that should represent the toxic intermediates responsible for subsequent reactions leading to plasmodium death. The three-dimensional structural requirements necessary for the activity of these new classes of antimalarial agents have been identified and discussed throughout the chapter.

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Notes

  1. 1.

    Both 3,4-cis and 3,4-trans esters 4 possessing one methyl substituent on C3 (R1 = Me) and two propyl substituents on C6 (R2 and R3 = n-propyl), resulted completely inactive (IC50 > 10 mM) against D10 and W2 Pf strains.

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Acknowledgments

The content of this chapter was reproduced from references: Persico et al. (2013) with permission from Elsevier (http://dx.doi.org/10.1016/j.ejmech.2013.10.050); Chianese et al. (2014) with permission from Elsevier (http://dx.doi.org/10.1016/j.bmc.2014.07.034); Lombardo et al. (2014) with permission from Wiley-VCH Verlag GmbH & Co. KGaA (http://dx.doi.org/10.1002/ejoc.201301394); Sonawane et al. (2015) with permission from the Royal Society of Chemistry (http://dx.doi.org/10.1039/c5ra10785g); Imperatore et al. (2015) with permission from the Royal Society of Chemistry (http://dx.doi.org/10.1039/c5ra09302c). This work was supported by the following grants: POR Campania FESR 2007–2013 FARMABIONET (B25C1300023007), MIUR—FIRB 2012 RBFR12WB3W, and EU Project Bluegenics (Grant 311848).

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  1. Department of Pharmacy, University of Napoli “Federico II”, Via D. Montesano 49, 80131, Naples, Italy

    Caterina Fattorusso, Marco Persico, Francesca Rondinelli, Nausicaa Orteca & Antonio Di Dato

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  1. Caterina Fattorusso
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Correspondence to Caterina Fattorusso .

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  1. ERC Advanced Investigator Group, Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Werner E. G. Müller

  2. ERC Advanced Investigator Group, Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Heinz C. Schröder

  3. ERC Advanced Investigator Group, Institute for Physiological Chemistry, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

    Xiaohong Wang

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Fattorusso, C., Persico, M., Rondinelli, F., Orteca, N., Di Dato, A. (2017). Computer-Aided Drug Discovery from Marine Compounds: Identification of the Three-Dimensional Structural Features Responsible for Antimalarial Activity. In: Müller, W., Schröder, H., Wang, X. (eds) Blue Biotechnology. Progress in Molecular and Subcellular Biology(), vol 55. Springer, Cham. https://doi.org/10.1007/978-3-319-51284-6_4

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