Apelin, a peptide produced in the heart, liver, kidney, and brain activates the recently deorphanized Apelin J receptor, lowers blood pressure, improves heart function, and appears to protect against nerve degeneration. Accelerated (GPU) NVT/NPT and replica exchange (REMD) molecular dynamics of solvated 17-length and shorter peptide fragments have been analyzed to examine correlations with candidates from a rich structure-activity landscape provided by medicinal chemistry and pharmacological characterizations. Analysis of molecular dynamics trajectories of solvated peptides in this study reveal: a) monotonic correlation of EC50 and % � turn character in the 'RPRL' region of the sequence corroborating, as previously suggested, that this a 'recognition'/activation motif in apelin peptides, b) a statistical correlation between hydrogen bonding between 'late-chain' amino acids with the 'RPRL' region with � turn character. Short peptides lacking activity are seen to lack significant � turn character (~= 20%) and requisite hydrogen bonding with late chain residues.

APJ receptor peptidomimetic design: Synthesis, simulation, pharmacophore, and pharmacological characterization

243rd National Meeting (2012)

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