Molecular Dynamics in Drug Design: New Generations of Compstatin Analogs

Authors

  • Phanourios Tamamis,

    1. Department of Bioengineering, University of California, Riverside, CA 92521, USA
    2. Department of Physics, University of Cyprus, PO20537, CY1678 Nicosia, Cyprus
    3. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
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    • Phanourios Tamamis is a visiting scholar at the University of California, Riverside and at Princeton University.

  • Aliana López de Victoria,

    1. Department of Bioengineering, University of California, Riverside, CA 92521, USA
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  • Ronald D. Gorham Jr,

    1. Department of Bioengineering, University of California, Riverside, CA 92521, USA
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  • Meghan L. Bellows-Peterson,

    1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
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  • Panayiota Pierou,

    1. Department of Physics, University of Cyprus, PO20537, CY1678 Nicosia, Cyprus
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  • Christodoulos A. Floudas,

    Corresponding author
    1. Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA
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  • Dimitrios Morikis,

    Corresponding author
    1. Department of Bioengineering, University of California, Riverside, CA 92521, USA
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  • Georgios Archontis

    Corresponding author
    1. Department of Physics, University of Cyprus, PO20537, CY1678 Nicosia, Cyprus
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Corresponding authors: Georgios Archontis, archonti@ucy.ac.cy; Dimitrios Morikis, dmorikis@engr.ucr.edu; Christodoulos Floudas, floudas@titan.princeton.edu

Abstract

We report the computational and rational design of new generations of potential peptide-based inhibitors of the complement protein C3 from the compstatin family. The binding efficacy of the peptides is tested by extensive molecular dynamics-based structural and physicochemical analysis, using 32 atomic detail trajectories in explicit water for 22 peptides bound to human, rat or mouse target protein C3, with a total of 257 ns. The criteria for the new design are: (i) optimization for C3 affinity and for the balance between hydrophobicity and polarity to improve solubility compared to known compstatin analogs; and (ii) development of dual specificity, human-rat/mouse C3 inhibitors, which could be used in animal disease models. Three of the new analogs are analyzed in more detail as they possess strong and novel binding characteristics and are promising candidates for further optimization. This work paves the way for the development of an improved therapeutic for age-related macular degeneration, and other complement system-mediated diseases, compared to known compstatin variants.

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