Poster abstracts

Poster number 31 submitted by Katryna Cisek

Rational Design of Early Premortem Alzheimer’s Disease Diagnostic Agents

Katryna K. Cisek (Biophysics Graduate Program, Center for Molecular Neurobiology, Ohio State University), Jeff Kuret (Center for Molecular Neurobiology, Department of Molecular and Cellular Biochemistry, Ohio State University)

Abstract:
Alzheimer’s disease (AD) is a progressive neurodegenerative disease affecting over five million people in the United States. Despite its high prevalence, AD is definitively diagnosed only upon autopsy. Recently, whole brain imaging has been developed to reveal the spatial distribution of biological targets. The key challenge in extending this approach to detect neurofibrillary lesions is the ability of small molecules to selectively bind tau aggregates.
To identify the major sources of binding affinity for protein filaments, a family of 50 benzothiazole derivatives disclosed in the patent literature was investigated using a computational approach. The published values for compound potency on synthetic aggregates composed of Aβ peptide and insulin (quantified as the ability to displace Thioflavin T, a fluorescent probe of protein aggregation) were rationalized in terms of calculated molecular properties using both partial and multiple least squares (PLS, MLS) regression methods.
Correlation of over 280 molecular properties through PLS analysis identified molecular polarizability, hydrophobicity, valence connectivity (related to dipole moment), and the rotatable bond fraction as the top-ranked determinants of binding affinity. MLS revealed that the correlation coefficient for calculated vs. measured potency exceeded 0.7 when these four descriptors were employed to build the structure activity relationship. The analysis revealed that polarizability and hydrophobicity were most important for generating differential binding affinity for Aβ relative to insulin filaments (p ≤ 0.01, and 0.001, respectively).
By developing a QSAR model that reflects the nature of the binding interaction, we have elucidated the key characteristics of high-affinity molecular probes. The compounds display a particular electronic configuration forming a Donor-π-Acceptor (D-π-A) system that allows delocalized electrons to participate in strong Van der Waals interactions. This dispersion-driven binding event can be maximized with more efficient D-π-A structures. As such, our approach and methodology should provide insight into the rational design of molecular probes for early pre-mortem AD diagnostic agents.

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Keywords: Alzheimers disease, QSAR model, rational diagnostic design