Design of new Alzheimer’s drugs using human’s complex of Aricept by cheminformatics analysis of molecular dynamics simulation

Alzheimer s Disease (AD) is a type of dementia that causes problems with memory, thinking andbehavior. Symptoms usually develop slowly and get worse over time, becoming severe enough tointerfere with daily tasks. The development of acetylcholinesterase (AChe) inhibitor drugs has followedthe finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD.The X-ray crystal structure of human AChe in complex with Aricept (a potent and specific inhibitorofAChe) has been recently released in protein data bank with the PDB code of 4EY7. To regard theflexibility of the enzyme in the process of rational drug design, a 100 ns molecular dynamics simulationof this complex has been carried out using the AMBER simulation program. The trajectory then wasclustered to output 10 representative structures of the complex to account the flexibility of the protein inthe process of drug design. The resulted structures were used as the input to the Pharmit server to screenthe NCI library by constructing structure based pharmacophre models. Shape filters for protein and ligandand also Lipinski rule of five were used to filter the output of virtual screening from pharmacophoremodels. The pharmacokinetic studies of the retrieved hits from the screening were carried out byregarding different critical factors like solubility, and blood brain barrier. The acceptable compoundswere then docked into the protein structure using sminato investigate the important interactions and fiveligands showing appropriate interactions with the target were subjected to experimental studies.

کلیدواژه ها:

Acetylcholinesterase ، Pharmacophore ، Molecular dynamics simulation ، Aricept ، Pharmit