Molecular docking combined with a consensus scoring function to predict protein-ligand affinity and ligand-based pharmacophore search for new drug scaffolds: an application for acetylcholinesterase inhibition

• Main Authors: Shin-Hua lu, 呂欣樺
• Other Authors: 劉宣良
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/rhr4xr

碩士 === 國立臺北科技大學 === 生物科技研究所 === 99 === Alzheimer’s disease is the most common cause of dementia characterized by progressive cognitive impairment in the elderly. It is a chronic, slowly progressive neurodegenerative disorder. The gradual loss of memory, decline in other cognitive functions, and decrease in functional capacity result in death approximately 8-10 years after the onset of the symptoms. It is accompanied by dysfunctions in the cholinergic neurotransmission of the central nervous system. Hence, most of the drugs approved for AD treatment are acetylcholinesterase inhibitors (AChEIs), which can enhance cholinergic neurotransmission by increasing acetylcholine availability in the synaptic cleft. In this study, molecular docking experiments combined with a consensus scoring function were conducted to predict the binding affinities of a total of 88 AChEIs, in which 68 and 20 compounds were used in the training and test sets, respectively, and to characterize the structural features of the catalytic gorge of acetylcholinesterase (AChE) toward binding. Our results yielded correlation coefficients R2 = 0.8439 and 0.9573 for the training and test sets, respectively, after partial least squares regression and leave-one-out cross-validation coefficient Q2 = 0.6291, indicating that the consensus scoring function developed here is applicable to bioactivity prediction and structural characterization for AChE inhibition. The identification of the protein-ligand interactions produces a list of those residues within the dual binding site of AChE, which make the most important hydrogen bond,