A substrate selectivity and inhibitor design lesson from the PDE10-cAMP crystal structure: A computational study

Justin Kai-Chi Lau, Xiao-Bo Li, Yuen-Kit Cheng

Research output: Contribution to journalJournal articlepeer-review

4 Citations (Scopus)
14 Downloads (Pure)

Abstract

Phosphodiesterases (PDEs) catalyze the hydrolysis of second messengers cAMP and cGMP in regulating many important cellular signals and have been recognized as important drug targets. Experimentally, a range of specificity/selectivity toward cAMP and cGMP is well-known for the individual PDE families. The study reported here reveals that PDEs might also exhibit selectivity toward conformations of the endogenous substrates cAMP and cGMP. Molecular dynamics simulations and free energy study have been applied to study the binding of the cAMP torsional conformers about the glycosyl bond in PDE10A2. The computational results elucidated that PDE10A2 is energetically more favorable in complex with the syn cAMP conformer (as reported in the crystal structure) and the binding of anti cAMP to PDE10A2 would lead to either a nonreactive configuration or significant perturbation on the catalytic pocket of the enzyme. This experimentally inaccessible information provides important molecular insights for the development of effective PDE10 ligands.

Original languageEnglish
Pages (from-to)5154-5160
Number of pages7
JournalJournal of Physical Chemistry B
Volume114
Issue number15
DOIs
Publication statusPublished - 22 Apr 2010

Scopus Subject Areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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