| The manifestation of every disease and disorder has its roots in the body's metabolic processes, and thus, in its endogenous factors. The ability to unveil these elusive factors and find their connection with the disease provides a rational and effective approach to drug discovery and disease treatment.; This thesis develops a library of all endogenous compounds in the brain and central nervous system with a molecular weight less than 1000 g/mol. Containing all neurotransmitters, amino acids, peptides, lipids, nucleotides, as well as components from every metabolic process known to take place in these types of cells, this endogenous library has been applied to two prevalent neurological disorders---epilepsy and Alzheimer's disease.; In the epilepsy study, five currently available epilepsy drugs are employed to produce an average active pharmacophore model of the common structural features that link them. The specifications of this averaged structure are used to screen the library for potential endogenous factors capable of suppressing seizures.; In the Alzheimer's study, a series of simple dianionic compounds were used to evaluate the geometric specifications of the active site of the Alzheimer's peptide, Abeta. The endogenous library was then screened based on these criteria to reveal a list of potential endogenous compounds capable of binding to the toxic beta-amyloid peptide. This list has been followed up by further in silico and in vitro binding studies.; The development of this endogenous library constitutes a novel conceptual development in drug design in which endogenous factors are studied in silico, prior to laborious, costly experimental techniques.; Furthermore, insights gained from the study of the disease at the metabolic level has led to the development of two new revolutionary theories on Alzheimer's disease. The first theory presents the idea that Alzheimer's is a multifactoral syndrome rather than a single disease, containing a common receptor throughout several of its associated proteins and peptides. The second theory states that Alzheimer's is an auto-immune disease of the innate immune system and the Abeta peptide is malfunctioning antimicrobial peptide. Both theories are explored computationally to develop these new conceptual approaches to viewing the disease. |
