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Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase.

ABSTRACT: The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands. Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). AutoDock version 3.0.5 has been widely distributed and successfully used to predict bound conformations of flexible ligands. Here, we also used a version of AutoDock which permits additional conformational flexibility in selected amino acid side chains of the target protein.

SUBMITTER: Morris GM

PROVIDER: S-EPMC3698963 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase.

Morris Garrett M GM Green Luke G LG Radić Zoran Z Taylor Palmer P Sharpless K Barry KB Olson Arthur J AJ Grynszpan Flavio F

Journal of chemical information and modeling 20130329 4

The use of computer-aided structure-based drug design prior to synthesis has proven to be generally valuable in suggesting improved binding analogues of existing ligands. Here we describe the application of the program AutoDock to the design of a focused library that was used in the "click chemistry in-situ" generation of the most potent noncovalent inhibitor of the native enzyme acetylcholinesterase (AChE) yet developed (K(d) = ~100 fM). AutoDock version 3.0.5 has been widely distributed and su ...[more]

PMID: 23451944

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Project description:Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.

Dataset Information

Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase.

Publications

Automated docking with protein flexibility in the design of femtomolar "click chemistry" inhibitors of acetylcholinesterase.

Similar Datasets

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