Pentameric models as alternative molecular targets for the design of new antiaggregant agents

EXEQUIEL BARRERA GUISASOLA; LUCAS JOEL GUTIÉRREZ; ANDUJAR SEBASTIAN; ANA MARIA RODRIGUEZ; RICARDO DANIEL ENRIZ

CURRENT PROTEIN AND PEPTIDE SCIENCE

BENTHAM SCIENCE PUBL LTD

Lugar: Oak Park; Año: 2016

1389-2037

The structure-based drug design has been an extremely useful technique used for searching and developing ofnew therapeutic agents in various biological systems. In the case of AD, this approach has been difficult to implement.Among other several causes, the main problem might be the lack of a specific stable and reliable molecular target. In thispaper the results obtained using a pentameric amyloid beta (Abeta) model as a molecular target are discussed. Our MDsimulations have shown that this system is relatively structured and stable, displaying a lightly conformational flexibilityduring 2.0 micros of simulation time. This study allowed us to distinguish characteristic structural features in specific regionsof the pentamer which should be taken into account when choosing this model as a molecular target. This represents aclear advantage compared to the monomer or dimer models which are highly flexible structures with large numbers ofpossible conformers. Using this pentameric model we performed two types of studies usually carried out on a moleculartarget: a virtual screening and the design on structural basis of new mimetic peptides with antiaggregant properties. Ourresults indicate that this pentameric model might be a good molecular target for these particular studies of molecularmodeling. Details about the predictive power of our virtual screening as well as about the molecular interactions thatstabilize the mimetic peptide-pentamer A-beta complexes are discussed in this paper