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UMBC High Performance Computing Facility
In silico screening of library of CNS bioavailable compounds to identify potential Aβ toxicity inhibitors
Theresa Good, Ben Keshet, Department of Chemical and Biochemical Engineering
β-Amyloid (Aβ) protein aggregates are the main constituents of the senile
plaque found in brains of Alzheimer's disease patients. The mechanism by Aβ induces a
wide range of biological phenomena in neuronal cells is mostly unknown. In our lab we have
recently found a specific region of Aβ protein that plays a role in Aβ binding to
cell membrane, and is the binding site of several known toxicity inhibitors. Elucidation
of new molecules that bind at locations of biological significance on Aβ may provide
new candidates for therapeutics for Alzheimer's disease. To that end, we are now
interested in virtually screening a library of small molecules for their ability to bind to
Aβ aggregates at the location we have found to be important for membrane binding. The
library of ~350,000 molecules was taken from the ZINC database, and is composed of
molecules that are likely capable of crossing the blood-brain-barrier. The NMR structure
of the Aβ fibril will be used as the receptor for binding. The energy of binding of
the molecules in the library to Aβ will be estimated using DOCK (UCSF). The molecules
will be then ranked according to their DOCK binding energies. The top 100 molecules from
computational docking will be tested experimentally in-vitro using SH-SY5Y cells for
potency as Aβ toxicity inhibitors. To the best of our knowledge this would be the
first virtual screening of toxicity inhibitors of Aβ.