(Drug Design Of AChE Inhibitors For Alzheimer’s Disease)

To investigate the quantitative relationship between the AChE inhibition of3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-8-y1)-1-propanones and their structures, and discover the interactions between these compounds and AChE, in order to obatian information for the design of novel compounds, a quantitative structure-activity relationship (QSAR) study has been carried out on acetylcholinesterase (AChE) inhibitors with comparative field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and hologram quantitative structure-activity relationship (HQSAR). In order to investigate the effect of alignment on modeling and find out the best alignment strategy, three different alignment rules namely Database alignment, Multi-fit alignment and Atom-fit alignment were applied to generate CoMFA and CoMSIA models. In order to investigate the effect of alignment on modeling and find out the best alignment strategy, three different alignment rules were applied to generate CoMFA and CoMSIA models. Statistical results of the highly significant models (q2>0.5, r2>0.9, r2predicted>0.5) reveal considerable predictive ability. The QSAR model developed by atom-fit alignment shows more excellent statistical values than the ones using two other alignment methods. Analysis of the contour maps of CoMFA and CoMSIA models and the atomic contribution maps of HQSAR model may contribute to develop novel and potential AChE inhibitors.According to the information of structure modification from the best QSAR models,1228novel compounds were designed based on the bioisostere. The virtual screening of these compounds were undertaken by follow options:(1) compounds with higher inhibition activities predicted by these three QSAR models were selected.(2) The pKa and logP values of the compounds with high activities via software of LABACD6.0, and then these compounds were analyzed with "five rules of analog drugs".(3) The rest of172compounds were put into the Discovery Studio2.5for the ADMET analysis, and26compounds with good pharmacokinetic properties and less toxic were obtained.(4) Finally, the molecular docking of these compounds with AChE was carried out to reveal interactions between them and receptor, also provide information for further structural optimization.The X-ray diffraction structure of AChE and ligands were reported in the form of TcAChE/mAChE-known drugs (AChE inhibitors) and hAChE-other structures (non-drug). Therefore, The AChE extracted from hAChE (2WPH) was selected as the receptor for the molecular docking with the ligands.Results of with the existing drugs (Tacrine, donepezil, galantamine and Huperzine A) show that the receptor-ligand interactions such as hydrogen bond andπ-π interactions are consistent with the literature, the same as the docking of hAChE with the most active compound in training set and the new designed comopunds.