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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
Park, Hwangseo; Lee, Hye; Ku, Bonsu; Lee, Sang-Rae; Kim, Seung
- 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 Mg 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 Mg 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.
- Subjects
PHOSPHATASES; NEURONAL differentiation; HUNTINGTON disease; ALLOSTERIC regulation; ATOMIC charges
- Publication
Journal of Computer-Aided Molecular Design, 2017, Vol 31, Issue 8, p743
- ISSN
0920-654X
- Publication type
Article
- DOI
10.1007/s10822-017-0037-2