Date of Award

9-8-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Information Science

First Advisor

Robert J. Shmookler Reis

Abstract

Cytotoxic protein aggregation is characteristic of age-associated neurological disorders such as Alzheimer's disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD). This thesis focused on identification of small molecules that are effective at reducing cytotoxic protein aggregation as potential drugs for treatment of neurodegenerative diseases. SH-SY5Y-APPSw neuroblastoma cells were used as a model of amyloidopathy to identify lead candidates. The lead candidates were further characterized in Caenorhabditis elegans strains CL4176 (an AD model that accrues amyloid deposits and develops progressive paralysis with age), and AM141 (a model of HD-like aggregation, which displays fluorescent aggregates in muscle followed by progressive paralysis). Also, part of this doctoral research examined protein-drug interactions through the use of Bioinformatics & Computational Biology tools (such as Schrödinger Maestro, Modeller, Desmond, Raccoon, AutoDock Vina, Sybyl, and GROMACS, all managed through a Linux interface) for molecular modeling, docking and molecular-dynamic simulations to address important drug development questions from the computational perspective. Further, a pipeline that incorporated several machine learning algorithms was designed, implemented and validated in R statistical software for QSAR modeling. Through the pipeline, dose-response data were correlated with molecular properties of the small molecules to define quantitative structure-activity relationships (QSAR). The structural features responsible for the anti-aggregative activity of the compounds were identified for the quinoline family of small molecules, thereby guiding further synthesis and testing of more potent second generation anti-aggregative small molecules for AD and related other protein aggregation-mediated diseases. Aggregation was assessed relative to untreated controls, in both SH-SY5Y-APPSw human neuroblastoma cells and C. elegans strains AM141 and CL4176. Our data are consistent with protection, by these anti-inflammatory compounds, against protein aggregation and associated traits. Our results provide a basis for considering anti-inflammatory drugs and related compounds as novel therapeutic agents to prevent or treat protein-aggregation disorders.

Download

Share

COinS