Pentameric Models as Alternative Molecular Targets for the Design of New Antiaggregant Agents

Abstract

The structure-based drug design has been an extremely useful technique used for searchingand developing of new therapeutic agents in various biological systems. In the case of AD, this approachhas been difficult to implement. Among other several causes, the main problem might be thelack of a specific stable and reliable molecular target. In this paper the results obtained using a pentamericamyloid beta (Aβ) model as a molecular target are discussed. Our MD simulations have shown that this system isrelatively structured and stable, displaying a lightly conformational flexibility during 2.0 μs of simulation time. This studyallowed us to distinguish characteristic structural features in specific regions of the pentamer which should be taken intoaccount when choosing this model as a molecular target. This represents a clear advantage compared to the monomer ordimer models which are highly flexible structures with large numbers of possible conformers. Using this pentamericmodel we performed two types of studies usually carried out on a molecular target: a virtual screening and the design onstructural basis of new mimetic peptides with antiaggregant properties. Our results indicate that this pentameric modelmight be a good molecular target for these particular studies of molecular modeling. Details about the predictive power ofour virtual screening as well as about the molecular interactions that stabilize the mimetic peptide-pentamer Aβ complexesare discussed in this paper