1. Evaluation of Novel Dual Acetyl- and Butyrylcholinesterase Inhibitors as Potential Anti-Alzheimer’s Disease Agents Using Pharmacophore, 3D-QSAR, and Molecular Docking Approaches
- Author
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Guanhua Du, Shilun Yang, Hui Fu, Song Wu, Xiaocong Pang, Lin Wang, and Ai-Lin Liu
- Subjects
Models, Molecular ,0301 basic medicine ,Quantitative Structure-Activity Relationship ,Pharmaceutical Science ,Analytical Chemistry ,chemistry.chemical_compound ,DL0410 ,0302 clinical medicine ,Drug Discovery ,Butyrylcholinesterase ,Molecular Structure ,biology ,Acetylcholinesterase ,Molecular Docking Simulation ,Chemistry (miscellaneous) ,language ,Molecular Medicine ,Piperidine ,Pharmacophore ,Alzheimer’s disease ,Protein Binding ,Quantitative structure–activity relationship ,Aché ,Stereochemistry ,Article ,lcsh:QD241-441 ,03 medical and health sciences ,lcsh:Organic chemistry ,Alzheimer Disease ,cholinesterase inhibitor ,Humans ,Physical and Theoretical Chemistry ,3D-QSAR ,Cholinesterase ,Binding Sites ,Organic Chemistry ,Rational design ,molecular docking ,language.human_language ,High-Throughput Screening Assays ,Kinetics ,kinetics ,030104 developmental biology ,Anti-Anxiety Agents ,chemistry ,biology.protein ,Cholinesterase Inhibitors ,030217 neurology & neurosurgery - Abstract
DL0410, containing biphenyl and piperidine skeletons, was identified as an acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor through high-throughput screening assays, and further studies affirmed its efficacy and safety for Alzheimer’s disease treatment. In our study, a series of novel DL0410 derivatives were evaluated for inhibitory activities towards AChE and BuChE. Among these derivatives, compounds 6-1 and 7-6 showed stronger AChE and BuChE inhibitory activities than DL0410. Then, pharmacophore modeling and three-dimensional quantitative structure activity relationship (3D-QSAR) models were performed. The R2 of AChE and BuChE 3D-QSAR models for training set were found to be 0.925 and 0.883, while that of the test set were 0.850 and 0.881, respectively. Next, molecular docking methods were utilized to explore the putative binding modes. Compounds 6-1 and 7-6 could interact with the amino acid residues in the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE/BuChE, which was similar with DL0410. Kinetics studies also suggested that the three compounds were all mixed-types of inhibitors. In addition, compound 6-1 showed better absorption and blood brain barrier permeability. These studies provide better insight into the inhibitory behaviors of DL0410 derivatives, which is beneficial for rational design of AChE and BuChE inhibitors in the future.
- Published
- 2017