A simple, yet highly accurate, QSAR model captures the complement inhibitory activity of compstatin

Chandrika Mulakala, John D. Lambris, Yiannis Kaznessis

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Compstatin is a 13-residue cyclic peptide inhibitor of complement activation that was originally identified through phage-mediated presentation of a peptide library to C3b. Recent efforts to improve its activity have led to a rich dataset of complement analogs, with the most active analog being ∼260 times more active than the parent compstatin. In the present work, a highly transparent quantitative structure-activity relationship model (Radj2 = 0.89) with four parameters is presented that captures important physico-chemical and geometrical properties of the analog molecules with regard to activity. The number of aromatic bonds and hydrophobicity of the fourth residue of compstatin correlated strongly with activity. Also important were the hydrophobic patch size near the disulfide bond and the solvent-accessible surface area occupied by nitrogen atoms of basic amino acid residues.

Original languageEnglish (US)
Pages (from-to)1638-1644
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number4
DOIs
StatePublished - Feb 15 2007

Bibliographical note

Funding Information:
We also thank Deborah McClellan for editorial assistance. This work was supported by NIH Grants GM 62134 and GM 069736.

Keywords

  • C3
  • Complement
  • Compstatin
  • QSAR
  • Structure-activity relationships

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