Development and characterization of cyclic analogs of apelin-13 through replica-exchange molecular dynamics and experimental validation

COMP 182

N. J. Maximilian Macaluso,, Sarah L. Pitkin2, Paul N. Sanderson3, Anthony P. Davenport2, and Robert C. Glen1. (1) Unilever Centre For Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom, (2) Clinical Pharmacology Unit, Department of Medicine, University of Cambridge, Addenbrookes Hospital, Cambridge, CB2 0SP, United Kingdom, (3) Measurement Science, Unilever, Colworth Science Park, Sharnbrook, MK44 1LQ, United Kingdom
The peptide apelin-13 (QRPRLSHKGPMPF) has recently been identified as the endogenous ligand of APJ, a G-Protein Coupled Receptor. The binding of this peptide causes a signal cascade that modulates many physiological responses, including vasoconstriction, HIV infection, and tumor neoangiogenesis [1]. The discovery of pharmacological probes of this receptor is vital to elucidate function but has been hampered by a lack of structural information. We present a ligand-based approach involving the design and characterization of cyclic analogues of apelin-13. These peptides provide insight into the binding requirements of APJ. Replica-exchange molecular dynamics as implemented in GROMACSv3.3.1 was used to explore the conformational space of these peptides incorporating NMR derived distance restraints from NOE measurements. The results provide insight into structural features necessary for binding. The computational data is supplemented with experimental validation through vasoconstrictor studies on endothelium denuded human saphenous vein.

[1] Sorli, SC, et. al. Drug Discovery Today, 1996: 11(23/24), 1100-1106.


Drug Discovery
8:30 AM-12:10 PM, Wednesday, March 25, 2009 Salt Palace Convention Center -- 257, Oral

Division of Computers in Chemistry

The 237th ACS National Meeting, Salt Lake City, UT, March 22-26, 2009