Potential Alzheimer's Disease Drug Target Identified

In findings with the potential to provide a therapy for Alzheimer's disease patients where none now exist, a researcher at the University of California, San Diego and colleagues have demonstrated in mice a way to reduce the overproduction of a peptide associated with the disease. The study, which showed substantial improvement in memory in an animal model of Alzheimer's disease, was led by Vivian Y. H. Hook, Ph.D., professor of the Skaggs School of Pharmacy and Pharmaceutical Sciences and professor of neurosciences, pharmacology and medicine at the UCSD School of Medicine, together with American Life Science Pharmaceuticals of San Diego. The study will be published in the March 21 edition of the Journal of Biological Chemistry, online March 14.

A hallmark sign of Alzheimer's disease, seen during autopsy of a patient's brain, is the accumulation of amyloid plaque deposits composed primarily of the neurotoxic beta-amyloid (Aβ) peptide which is believed to be a major factor in the cause of the disease. The Aβ peptides are "cut" out from a larger protein called the amyloid precursor protein (APP) and bind together to form plaques in brain regions responsible for memory. One drug strategy to fight Alzheimer's disease is to reduce production of Aβ."We discovered two chemical compounds that inhibit a new enzyme target, leading to reduced production of beta amyloid and improved memory in a mouse model of Alzheimer's disease," said Hook.

MOLECULAR DOCKING

Docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex. Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinity between two molecules using for example scoring functions

Applications: A binding interaction between a small molecule ligand and a enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism. Docking is most commonly used in the field of drug design - most drugs are small organic molecules, and docking may be applied to

Hit identification - docking combined with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest.
Lead optimization - docking can be used to predict in where and in which relative orientation a ligand binds to a protein (also referred to as the binding mode or pose). This information may in turn be used to design more potent and selective analogs

Docking Programs

1.AUTODOCK
2.DOCK
3.GOLD
4.ARGULAB
5.AMBER