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 non-covalent inhibitor of the enzyme acetylcholinesterase (AChE) yet developed (Kd = ~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 current version of AutoDock which permits additional conformational flexibility in selected amino acid sidechains of the target protein.
SourceAvailable from: Jandeep Singh[Show abstract] [Hide abstract]
ABSTRACT: A concise and useful synthesis of novel 1,2,3-triazole based silatrane (TBS)-scaffolds (2a–e) in good yield from 1,2,3-triazole based triethoxysilane (TBTES)-linkers (1a–e) is described. Click silylation of terminal alkynes with γ-azidopropyltriethoxysilane (AzPTES) was used for the synthesis of TBTES-linkers (1a–e). The synthesized TBS-scaffolds (2a–e) were comprehensively characterized by 1H and 13C NMR, mass spectrometry and single X-ray crystallographic studies. The broad scope of these TBS-scaffolds towards biogenic amines is explored by the use of a CH3CN:H2O (98:2; v/v) solvent system. The receptor 2c and 2d shows high affinity towards spermine and histamine, respectively. To the best of our knowledge, the present investigation represents the first report on the use of organosilicon-based chemosensors for the recognition of biogenic amines.RSC Advances 08/2014; 4(69). DOI:10.1039/C4RA02270J · 3.71 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Krabbe disease or globoid cell leukodystrophy is a degenerative, lysosomal storage disease resulting from the deficiency of β-galactocerebrosidase activity. This enzyme catalyzes the lysosomal hydrolysis of galactocerebroside and psychosine. Krabbe disease is inherited as an autosomal recessive trait, and many of the 70 disease-causing mutations identified in the GALC gene are associated with protein misfolding. Recent studies have shown that enzyme inhibitors can sometimes translocate misfolded polypeptides to their appropriate target organelle bypassing the normal cellular quality control machinery and resulting in enhanced activity. In search for pharmacological chaperones that could rescue the β-galactocerebrosidase activity, we investigated the effect of α-Lobeline or 3',4',7-trihydroxyisoflavone on several patient-derived fibroblast cell lines carrying missense mutations, rather than on transduced cell lines. Incubation of these cell lines with α-lobeline or 3',4',7-trihydroxyisoflavone leads to an increase of β-galacocerebrosidase activity in p.G553R+p.G553R, in p.E130K+p.N295T and in p.G57S+p.G57S mutant forms over the critical threshold. The low but sustained expression of β-galactocerebrosidase induced by these compounds is a promising result; in fact, it is known that residual enzyme activity of only 15-20% is sufficient for clinical efficacy. The molecular interaction of the two chaperones with β-galactocerebrosidase is also supported by in silico analysis. Collectively, our combined in silico-in vitro approach indicate α-lobeline and 3',4',7-trihydroxyisoflavone as two potential pharmacological chaperones for the treatment or improvement of quality of life in selected Krabbe disease patients.Molecular Genetics and Metabolism 05/2014; DOI:10.1016/j.ymgme.2014.05.009 · 2.83 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Figure 5(a) in our paper Our proposed inhibitor to BChE, which can bind strongly to BChE. The introduced group into K25 is indicated by a red dashed ellipse.Journal of Molecular Graphics and Modelling 09/2014; DOI:10.1016/j.jmgm.2014.09.002 · 2.02 Impact Factor