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. 2008 Oct;72(4):249-56.
doi: 10.1111/j.1747-0285.2008.00709.x.

Development of a New Pharmacophore Model That Discriminates Active Compstatin Analogs

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Free PMC article

Development of a New Pharmacophore Model That Discriminates Active Compstatin Analogs

Ting-Lan Chiu et al. Chem Biol Drug Des. .
Free PMC article

Abstract

Compstatin and its active peptide analogs can potentially be used for therapeutic purposes because their binding to the third component of complement prohibits its conversion into the proteolytically activated form of the third component of complement, thus inhibiting complement cascades in all three complement pathways. Mallik and Morikis built three quasi-dynamic pharmacophore models for compstatin peptide analogs before, but only nine compstatin peptide analogs were incorporated in their study and the most active compstatin analog had only medium inhibitory activity. Since then, many more compstatin analogs have been synthesized and their inhibitory activities tested. Furthermore, the X-ray structure of AcCompNH2-V4W-H9A bound to the third component of complement has become available (PDB ID: 2QKI). In this paper, we utilized all the new information and built a new pharmacophore model using a distinct approach. Our model demonstrated good performance in a separate test set of 82 compstatin analogs: it accurately identified 70% of the analogs of medium or high inhibitory activities and misclassified only 8.5% of the analogs of low or no inhibitory activities. The results proved our pharmacophore model to be a filter of great sensitivity and specificity.

Figures

Figure 1
Figure 1
Snapshots of four comstatin analogs illustrating specific interactions that stabilize the interactions with C3. Compstatin is colored in green. Its residues are labeled in yellow. C3 is colored in grey. Its residues are labeled in white. The hydrogen bonds are shown in dotted yellow lines.
Figure 2
Figure 2
The superposition of the six pharmacophore features over the aligned structures of the two most active compstatin analogs, AcCompNH2-V4(1MeW)-H9A and AcCompNH2-V4(1MeW)-W7(5fW)-H9A. Aro: Aromatic ring center. Acc: Hydrogen-bond acceptor. Don: Hydrogen-bond donor. Hyd: Hydrophobic region.

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