5 research outputs found
Short amyloidogenic stretches as triggers of amyloid fibril formation and targets for the design of antiamyloid agents
Tesis doctoral inĂ©dita leĂda en la Universidad AutĂłnoma de Madrid, Facultad de Ciencias, Departamento de BiologĂa Molecular. Fecha de lectura: 20-12-200
A Molecular Dynamics Study of the Interaction of D-Peptide Amyloid Inhibitors with Their Target Sequence Reveals a Potential Inhibitory Pharmacophore Conformation
The self-assembly of soluble proteins and peptides into beta-sheet-rich
oligomeric structures and insoluble fibrils is a hallmark of a large
number of human diseases known as amyloid diseases. Drugs that are able
to interfere with these processes may be able to prevent and/or cure
these diseases. Experimental difficulties in the characterization of the
intermediates involved in the amyloid formation process have seriously
hampered the application of rational drug design approaches to the
inhibition of amyloid formation and growth. Recently, short model
peptide systems have proved useful in understanding the relationship
between amino acid sequence and amyloid formation using both
experimental and theoretical approaches. Moreover, short D-peptide
sequences have been shown to specifically interfere with those short
amyloid stretches in proteins, blocking oligomer formation or
disassembling mature fibrils. With the aim of rationalizing which
interactions drive the binding of inhibitors to nascent beta-sheet
oligomers, in this Study, we have carried out extensive molecular
dynamics simulations of the interaction of selected D-peptide sequences
with oligomers of the target model sequence STVIIE. Structural analysis
of the simulations helped to identify the molecular determinants of an
inhibitory core whose conformational and physicochemical properties are
actually shared by nonpeptidic small-molecule inhibitors of
amyloidogenesis. Selection of one of these small molecules and
experimental validation against our model system proved that it was
indeed an effective inhibitor of fibril formation by the STVIIE
sequence, supporting theoretical predictions. We propose that the
inhibitory determinants derived from this work be used as structural
templates in the development of pharmacophore models for the
identification of novel nonpeptidic inhibitors of aggregation. (C) 2008
Elsevier Ltd. All rights reserved