Drug repositioning based anti-alzheimer drug discovery and in vitro evaluation

Due to the high time and cost involved of conventional drug development methods, there is a need for more efficient methods in terms of time and cost. Alzheimer's disease (AD) is a neurodegenerative disease for which effective drugs are still needed and which is treated symptomatically. Drug repositioning is a method of drug discovery based on the principle of using existing drugs beyond their original therapeutic purpose for the treatment of other diseases or for new indications. This perspective creates a safer profile as it involves the re-evaluation of existing drugs with already known pharmacokinetic, toxicological and safety data. In this context, the main objective of this work is to identify potential drug candidates for Alzheimer's disease using the drug repositioning strategy. In the first phase, gene expression profiles of Alzheimer's disease were generated using the NCBI GEO database and drug candidates were identified using the cMAP platform. At the end of this phase, dehydroisoadosterone, moricizine, SKF-96365, KU-0063794, ouabain, proscillaridin A, digoxin, WYE-354, MK-212, parbendazole and cinobufagin were selected as candidate molecules. In the second phase, an in vitro evaluation was performed by conducting an acetylcholinesterase enzyme inhibition study for the identified potential drugs. The compounds tested showed IC50 values between 31.181 nM-113.134 nM (standard compound tacrine: 33.052 nM) and Ki values between 8.065± 4.700 nM-123.164±92.915 nM (standard compound tacrine: 7.177±4.429). This dissertation study presented an innovative approach to expand the available treatment options for Alzheimer's disease. Keywords: Drug repositioning, Alzheimer's disease, CmAp, Drug discovery, Acetylcholinesterase