http://dx.doi.org/10.1021/jp911156g">
 

Document Type

Journal Article

Department/Unit

Department of Chemistry

Title

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

Language

English

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. © 2010 American Chemical Society.

Publication Date

2010

Source Publication Title

Journal of Physical Chemistry B

Volume

114

Issue

15

Start Page

5154

End Page

5160

Publisher

American Chemical Society

ISSN (print)

15206106

ISSN (electronic)

15205207

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