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Title 

Two-track virtual screening approach to?identify both?competitive and?allosteric inhibitors of?human small C-terminal domain phosphatase 1

Authors 

H ParkHye Seon LeeBonsu KuSang-Rae LeeSeung Jun Kim

Publisher 

Springer Verlag (Germany)

Issue Date 

2017

Citation 

Journal of Computer Aided Molecular Design

Keywords 

Allosteric inhibitorCompetitive inhibitorDockingSmall C-terminal domain phosphatase 1Virtual screening

Abstract 

Despite a wealth of persuasive evidence for the involvement of human small C-terminal domain phosphatase 1 (Scp1) in the impairment of neuronal differentiation and in Huntington’s disease, small-molecule inhibitors of Scp1 have been rarely reported so far. This study aims to the discovery of both competitive and allosteric Scp1 inhibitors through the two-track virtual screening procedure. By virtue of the improvement of the scoring function by implementing a new molecular solvation energy term and by reoptimizing the atomic charges for the active-site Mg2+ ion cluster, we have been able to identify three allosteric and five competitive Scp1 inhibitors with low-micromolar inhibitory activity. Consistent with the results of kinetic studies on the inhibitory mechanisms, the allosteric inhibitors appear to be accommodated in the peripheral binding pocket through the hydrophobic interactions with the nonpolar residues whereas the competitive ones bind tightly in the active site with a direct coordination to the central Mg2+ ion. Some structural modifications to improve the biochemical potency of the newly identified inhibitors are proposed based on the binding modes estimated with docking simulations

ISSN 

0920-654X

Link 

http://dx.doi.org/10.1007/s10822-017-0037-2

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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