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5 results on '"Pierou, P."'

1. Molecular Dynamics in Drug Design: New Generations of Compstatin Analogs

Author

Tamamis, Phanourios, López de Victoria, A., Gorham, R. D., Bellows-Peterson, M. L., Pierou, P., Floudas, C. A., Morikis, D., Archontis, Georgios Z., Tamamis, Phanourios [0000-0002-3342-2651], and Archontis, Georgios Z. [0000-0002-7750-8641]

Subjects
crystal structure, drug design, Molecular Sequence Data, Molecular modeling, protein binding, Molecular Dynamics Simulation, Peptides, Cyclic, hydroxymethylglutaryl coenzyme A reductase inhibitor, Mice, binding affinity, physical chemistry, Humans, Animals, Animalia, rat, Mechanism-based drug design, human, mouse, hydrophobicity, Complement system, C3, hydrogen bond, nonhuman, Rattus, solubility, article, retina macula degeneration, X ray crystallography, molecular docking, Complement C3, molecular dynamics, amino acid sequence, unclassified drug, Rats, priority journal, protein stability, protein protein interaction, amino terminal sequence, Compstatin, protein secondary structure, Structure-based drug design, mutation
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. © 2012 John Wiley & Sons A/S. 79 5 703 718 Cited By :16

Published
2012

2. Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: The case of C3 inhibition by compstatin

Author

Tamamis, Phanourios, Pierou, P., Mytidou, C., Floudas, C. A., Morikis, D., Archontis, Georgios Z., Tamamis, Phanourios [0000-0002-3342-2651], and Archontis, Georgios Z. [0000-0002-7750-8641]

Subjects
Innate immune response, Models, Molecular, Primates, Complement system, ligand binding, Mice, Transgenic, Molecular dynamics, Molecular Dynamics Simulation, Ligands, Crystallography, X-Ray, Peptides, Cyclic, complement component C3, Mice, protein conformation, binding affinity, Compstatin analogs, Humans, Animals, Animalia, Mus musculus, human, protein interaction, Amino Acid Sequence, protein structure, Complement Activation, mouse, nonhuman, Rattus, article, compstatin, Complement C3, peptide, unclassified drug, priority journal, Mammalia, Peptides, C3 inhibitors, Sequence Alignment, Protein Binding
Abstract

The peptide compstatin and its derivatives inhibit the complement-component protein C3 in primate mammals and are potential therapeutic agents against the unregulated activation of complement in humans, but are inactive against C3 from lower mammals. Recent molecular dynamics (MD) simulations showed that the most potent compstatin analog comprised entirely of natural amino acids (W4A9) had a smaller affinity for rat C3, due to reproducible changes in the rat protein structure with respect to the human protein, which eliminated or weakened specific protein-ligand interactions seen in the human C3:W4A9 complex. Here, we study by MD simulations three W4A9 complexes with the mouse C3 protein, and two "transgenic" mouse derivatives, containing a small number (6-9) of human C3 substitutions. The mouse complex experiences the conformational changes and affinity reduction of the rat complex. In the "transgenic" complexes, the conformation remains closer to that of the human complex, the protein-ligand interactions are improved, and the affinity for compstatin becomes "human-like." The present work creates new avenues for a compstatin-sensitive animal model. A similar strategy, involving the comparison of a series of complexes by MD simulations, could be used to design "transgenic" sequences in other systems. © 2011 Wiley-Liss, Inc. 79 11 3166 3179 Cited By :14

Published
2011

4. Molecular dynamics in drug design: new generations of compstatin analogs.

Author

Tamamis P, López de Victoria A, Gorham RD Jr, Bellows-Peterson ML, Pierou P, Floudas CA, Morikis D, and Archontis G

Subjects
Amino Acid Sequence, Animals, Complement C3 chemistry, Complement C3 metabolism, Humans, Mice, Molecular Sequence Data, Peptides, Cyclic pharmacology, Rats, Complement C3 antagonists & inhibitors, Drug Design, Molecular Dynamics Simulation, Peptides, Cyclic chemistry
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., (© 2012 John Wiley & Sons A/S.)

Published
2012
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5. Design of a modified mouse protein with ligand binding properties of its human analog by molecular dynamics simulations: the case of C3 inhibition by compstatin.

Author

Tamamis P, Pierou P, Mytidou C, Floudas CA, Morikis D, and Archontis G

Subjects
Amino Acid Sequence, Animals, Complement Activation drug effects, Crystallography, X-Ray, Humans, Ligands, Mice, Mice, Transgenic, Models, Molecular, Molecular Dynamics Simulation, Peptides chemistry, Peptides, Cyclic genetics, Peptides, Cyclic metabolism, Protein Binding, Protein Conformation, Sequence Alignment, Complement C3 antagonists & inhibitors, Peptides, Cyclic chemistry
Abstract

The peptide compstatin and its derivatives inhibit the complement-component protein C3 in primate mammals and are potential therapeutic agents against the unregulated activation of complement in humans, but are inactive against C3 from lower mammals. Recent molecular dynamics (MD) simulations showed that the most potent compstatin analog comprised entirely of natural amino acids (W4A9) had a smaller affinity for rat C3, due to reproducible changes in the rat protein structure with respect to the human protein, which eliminated or weakened specific protein-ligand interactions seen in the human C3:W4A9 complex. Here, we study by MD simulations three W4A9 complexes with the mouse C3 protein, and two "transgenic" mouse derivatives, containing a small number (6-9) of human C3 substitutions. The mouse complex experiences the conformational changes and affinity reduction of the rat complex. In the "transgenic" complexes, the conformation remains closer to that of the human complex, the protein-ligand interactions are improved, and the affinity for compstatin becomes "human-like." The present work creates new avenues for a compstatin-sensitive animal model. A similar strategy, involving the comparison of a series of complexes by MD simulations, could be used to design "transgenic" sequences in other systems., (Copyright © 2011 Wiley-Liss, Inc.)

Published
2011
Full Text
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