Research Advances On New Hybrid Compounds Which Are Capable Of Being Used As Multi-target-directed Ligands In The Treatment Of Alzheimer's Disease


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DİNCEL E. D. , Ece A., Coşar E. D. , GÜZELDEMİRCİ N.

5th International Symposium On Multidisciplinary Studies, Ankara, Turkey, 16 - 17 November 2018, pp.872

  • Publication Type: Conference Paper / Full Text
  • City: Ankara
  • Country: Turkey
  • Page Numbers: pp.872

Abstract

Alzheimer’s Disease (AD) is an age-related and progressive neurodegenerative disorder of central nervous system (CNS) affecting more than 35 million people worldwide. This number is expected to sharply increase beyond 107 million by the year 2050. At the present time, this disease is the most common type of advancing brain neurodegeneration and the main cause of dementia. Alzheimer’s Disease (AD), characterized by memory loss and other cognitive impairments, is currently one of the most difficult and complicated diseases to treat because of its complicated and multifaceted etiology. Despite intensive studies, the pathophysiology and ethiology of Alzheimer’s disease have not been fully elucidated yet. In the past years, multiple pathogenesis hypotheses of the Alzheimer’s disease have been proposed, such as cholinergic hypothesis, amyloid cascade hypothesis, oxidative stress hypothesis, tau protein hypothesis and inflammation hypothesis. Among them, the cholinergic hypothesis was a widely accepted theory, which suggest that low level of ACh in spesific parts of the brain is the major reason results in learning and memory dysfunctions. Because of the AD is a complex neurodegenerative disorders resulting from multiple factors, molecules that modulate the activity of a single protein target might not be able to significantly changes the progression of the disease. In recent years, a multi-target-directed-ligand (MTDL) strategy has been developed to overcome this multifaceted disease. Based on the MTDL drug design strategy, scientists combined the pharmacophore groups of the drugs which are affecting different protein targets to a single molecular entity to obtain new multiple effected compounds. The multi-targetdirected ligand (MTDL) strategy is expected to provides preeminent effects for the treatment of AD, instead of the classic one-drug-one-target strategy. We conducted a study about examining all the molecules formed by multi-target-directed-ligand technology between 1970 and 2018. We investigated, with which level and in which step our molecule show biological activity against Alzheimer’s Disease. We evaluated the therapeutic activity of the molecules in detail. On the other hand, computer drug design tools potentially minimize time and cost in drug disdovery processes. Hence, we also carried out in silico simulations using Schrödinger software to determine binding modes of the compounds with the AChE target and also to calculate potential drug likeness and other properties that are related to absorption, distribution, metabolism, excretion, toxicity (ADMET) of those compounds. The overall results obtained from molecular modelling studies and the pharmacological responses of the molecules synthesized by multi-target-directed ligand technique can provide insight for the synthesis of the more efficient AChE inhibitors which might also have higher selectivity. In addition, the present study also provides scientists a wide data resource related to the treatment of Alzheimer’s disease and multi-target-directed-ligand (MTDL) strategy, thus helping them perform a more organized and fertile drug discovery operation.