Rauk, ArviOpare, Stanley2018-05-042018-05-042018-04-20Opare, S. K. A. (2018). In Silico Ligand Design to Inhibit Oligomerisation and Cu+ Redox Activity in Alzheimer’s Disease (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/31892http://hdl.handle.net/1880/106610Alzheimer’s disease (AD) is a progressive disease of the brain. It leads to the loss of memory and thinking abilities. The toxicity has been associated with smaller oligomeric forms of beta amyloid peptide (beta amyloid). The speed of aggregation has been attributed to pH changes attributing fastest aggregation to pH ranging from 5 to 6. Generation of reactive oxidative species (ROS) has also been attributed to the cause of this disease. This process has been attributed to Fenton-like chemistry involving copper. Cu+ has been associated with reduction of O2 to O2•-; reduction of O2•- to H2O2; and further reduction of H2O2 to form HO•. Because of these, Cu+ was targeted in designing ligands that will bind stronger Cu+ than how much beta amyloid will. Beta amyloid complexes Cu+ using His13 and His14. Using quantum mechanical (QM) approach, the binding energy of both oxidation states of copper bound to two histidines and additional water molecules to complete the coordination where necessary (to model the interaction in Ab) were generated and the reduction potential estimated. Armed with this information, ligands were designed that mimic the Cu+ coordination in beta amyloid. The Gibbs free energies of both Cu+ and Cu2+ coordination to these ligands in addition to their reduction potentials were also calculated and compared to that in the model beta amyloid complex. The ligands were ranked accordingly and possible drug (ligand) candidates predicted. One of the ligand candidates (PI) was attached to a pseudopeptide called SGC1 which was designed to inhibit oligomerization. Molecular dynamics and umbrella sampling approaches were used to ascertain their inhibition of beta amyloid self oligomerization. By so doing this new pseudopeptide will serve both purposes of inhibiting oligomerization and generation of reactive oxidative species. Due to computational cost the region of beta amyloid that was used was the so called self recognition site and the region that binds to Cu+. This region covers from His13 to Asp23. This region is referred to as Rec and is used as a model for beta amyloid.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.Education--Sciencesdoctoral thesis10.11575/PRISM/31892