期刊
MOLECULAR INFORMATICS
卷 35, 期 8-9, 页码 369-381出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/minf.201501033
关键词
Phosphodiesterases; PDE4; PDE4D selective inhibitors; docking; molecular dynamics
类别
资金
- Alzheimer Association [IIRG 11-208306]
- Italian Ministry of Education and Research through the Flagship InterOmics project [PB05]
- Italian Ministry of Education and Research through the HIRMA project [RBAP11YS7K]
- European MIMOmics project [305280]
Alzheimers disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D-MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in-house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D inhibition. The binding model disclosed within the current computational study may prove to be useful to further advance the design and synthesis of novel, more potent and selective, PDE4D inhibitors.
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