Molecular modeling, docking and ADMET studies applied to the design of a novel hybrid for treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of dementia in adults, which is characterized by senile plaquets and cholinergic deficit as the disease progresses. Improvement of cholinergic neurotransmission is the basis of some drugs currently used in the treatment of AD. It is achieved by acetylcholinesterase (AChE) inhibition, the enzyme responsible for acetylcholine hydrolysis. Molecular modeling techniques were of utmost importance to design a new pharmaceutical against Alzheimer's disease, with potential inhibitory activity over AChE, since the inhibition of human plasma butyrylcholinesterase (BChE) may cause side effects. Some of the drugs currently used in the treatment of AD are capable of increasing the cholinergic transmission through the AChE inhibition. In this work we proposed molecular hybrids of tacrine with donepezil (fusion of these structures), in order to suggest new proposals of AChE inhibitors for future treatment of AD. We have analyzed all the structures by docking, density functional studies and drug like properties.