Identification of first proadrenomedullin N-terminal 20 peptide (PAMP) modulator by means of virtual screening and NMR interaction experiments

PAMP (proadrenomedullin N-terminal 20 peptide) is a regulatory peptide that is detected in a large variety of cell types and exerts important biological activities. PAMP acts as a potent angiogenic factor and decorates microtubules in cells from different origins, controlling tubulin polymerization. A high-throughput docking-based virtual screening was performed, followed by a competitive monoclonal antibody assay on selected compounds, and a detailed 1H, 15N NMR spectroscopy study. This procedure has allowed us to describe the first small molecule capable of interacting with PAMP and potentially modulate its biological activity. Molecular modeling methods such as docking and molecular dynamics were carried out to obtain a theoretical model of binding mode. Finally a directed in vivo angiogenesis assay (DIVAA) showed that the small molecule by itself has pro-angiogenic properties.

Figure optionsDownload as PowerPoint slideHighlights
► PAMP (proadrenomedullin N-terminal 20 peptide) as a drug target.
► Virtual screening of the NCI chemical database against PAMP.
► Identification of the first Small Molecule interacting with PAMP.
► Molecular modeling combined with NMR experiments provided a model of the binding.
► In vivo analysis of small molecules for angiogenic activity.