Complement receptor C5aR is a member of the GPCR superfamily, and upon activation by complement anaphylatoxin C5a initiates a pro-inflammatory response. Over-activation of C5aR has been implicated in several inflammatory diseases such as atherosclerosis and abdominal aortic aneurism, and therefore has been the focus of numerous drug design efforts. In this study we employ implicit solvent/membrane molecular dynamics simulations to compare ten peptidic C5aR antagonists with varied levels of activity, including the highly potent analog PMX-53. Structure-based clustering using side chain torsion angles was performed to provide initial insight into the dynamic nature of C5aR antagonist activity. To further investigate the dynamic and physicochemical characteristics necessary for C5aR antagonist activity, probability distributions of distances, angles, and dihedral angles relating pharmacophore points were generated. Hierarchical clustering based on the comparison of the pharmacophore point distributions was used to classify the ten peptidic antagonists, and identify distinguishing characteristics of C5aR antagonist activity.

Development of a quasi-dynamic pharmacophore model for cyclic peptidic antagonists of complement receptor C5aR

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.