(246b) The Design of Beta Amino Acid Fragments to Inhibit the Aggregation of Alpha Synuclein

The aggregation of alpha synuclein is involved with Parkinson’s disease and is thought to lead to neural degeneration in the basal ganglia. It has been demonstrated that fragments of beta synuclein (ligands) can inhibit the aggregation of alpha synuclein. The goal of this project is to use computer aided molecular design (CAMD) to propose beta amino acid fragments that will inhibit the aggregation of alpha synuclein. If this aggregation can be inhibited, the disease process might be halted or reversed.

Neuro-active pharmaceuticals were analyzed to determine the physico-chemical property constraints that enable them to cross the blood brain barrier (BBB). We have modified a fitness function proposed for systemic drugs and use it within a CAMD framework to design beta amino acid fragments that cross the BBB and bind to targets on alpha synuclein. This bonding inhibits the protein from aggregating. Beta amino acids are used in this work as they are resistant to metabolism and can be administered orally. The chemical properties of the ligands that cause them to bind to alpha synuclein are the chemical property targets for the ligands in this project. These ligand to protein interactions are modeled using AutoDock Vina to identify those portions of the beta synuclein fragments that interact with alpha synuclein and where on the protein the interaction occurs.

The chemical properties derived from this initial work were combined within a CAMD frame work to develop prospective compounds. Due to the ease of synthesizing small protein fragments, fragments containing three and four beta amino acid residues were designed that would bind to the target areas of alpha synuclein.

A swarm based algorithm called the Artificial Bee Colony used molecular descriptor based models for the chemical characteristics of alpha synuclein to design beta protein fragments to inhibit aggregation of alpha synuclein. A selection of the beta amino acid fragments were studied using UV absorption to compare their ability to inhibit the aggregation of alpha synuclein using in vitro experimental methods. The change in UV absorption measures the initial steps in the progression of aggregation