Molecular Dynamics in Drug Design: New Generations of Compstatin Analogs

• Published in: Chemical biology & drug design Vol. 79; no. 5; pp. 703 - 718
• Main Authors: Tamamis, Phanourios, López de Victoria, Aliana, Gorham Jr, Ronald D., Bellows-Peterson, Meghan L., Pierou, Panayiota, Floudas, Christodoulos A., Morikis, Dimitrios, Archontis, Georgios
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2012
• Subjects: Amino Acid Sequence; Animals; Complement C3 - antagonists & inhibitors; Complement C3 - chemistry; Complement C3 - metabolism; complement system; complement system, C3; compstatin; Drug Design; Humans; mechanism-based drug design; Mice; Molecular Dynamics Simulation; molecular modeling; Molecular Sequence Data; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Rats; structure-based drug design
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2012.01324.x

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. The use of molecular dynamics in drug design is demonstrated, using compstatin family peptides as a paradigm. Analogs with novel properties are presented using the following design criteria: (i) optimization for high binding affinity and for the balance between hydrophobicity and polarity to improve solubility, compared to known compstatin analogs; and (ii) development of dual specificity antihuman‐rat/mouse C3 analogs, which is important for use in animal models for disease, given the species specificity of known compstatin analogs.