J Chem Inf Model - Acetylcholinesterase inhibitors: structure based design, synthesis, pharmacophore modeling, and virtual screening.


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Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer's disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure-activity relationship (QSAR) studies using a training set of 20 known compounds for which IC50 values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC50 values for a test set of 20 independent compounds with measured IC50 values. A correlation analysis was carried out comparing the statistics of the measured IC50 values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a-6j) and 5H-thiazolo[3,2-a] pyrimidines (7a-7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD.

Resumo Limpo

acetylcholinesteras ach main drug target inhibitor demonstr function symptomat treatment alzheim diseas ad studi seri novel ach inhibitor design inhibitori activ evalu d quantit structureact relationship qsar studi use train set known compound ic valu previous determin qsar model calcul base seven uniqu descriptor model valid determin predict ic valu test set independ compound measur ic valu correl analysi carri compar statist measur ic valu predict one selectivitydetermin descriptor interpret graphic term princip compon analys pca d pharmacophor model also creat base activ train set addit absorpt distribut metabol excret adm descriptor also determin evalu pharmacokinet properti final molecular dock novel molecul ach bind domain indic three molecul c c h signific higher affin solvat energi known standard drug donepezil dock studi hthiazoloapyrimidin aj hthiazoloa pyrimidin aj human ach demonstr ligand bind dual site enzym simpl ecofriend synthes diastereomer crystal hthiazolo apyrimidin hthiazoloa pyrimidin describ solidst structur hbr salt compound e determin use singlecryst xray diffract techniqu xray powder pattern measur bulk solid remain solvent remov solut contain studi provid valuabl insight design potent select inhibitor treatment ad

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