Abstract
Phosphodiesterase (PDE) enzymes regulate the levels of cyclic nucleotides, cAMP, and/or cGMP, being attractive therapeutic targets. In order to modulate PDE activity in a selective way, we focused our efforts on the search of allosteric modulators. Based on the crystal structure of the PDE10A GAF-B domain, a virtual screening study allowed the discovery of new hits that were also tested experimentally, showing inhibitory activities in the micromolar range. Moreover, these new PDE10A inhibitors were able to decrease the nitrite production in LPS-stimulated cells, thus demonstrating their potential as anti-inflammatory agents.
Highlights
Phosphodiesterases are the enzymes responsible for breaking down the cyclic nucleotides cGMP and/or cAMP, which are two of the most important signaling molecules in cells [1]
With the aim of overcoming off-target difficulties of the competitive inhibitors bound to the catalytic domain of these enzymes, here we proposed a structure-based virtual screening for the identification of novel candidates able to target the regulatory domain of PDE10A using its reported crystal structure [9]
In order to discover novel selective PDE10 inhibitors based on the GAF-B domain structure of human PDE10A (PDB: 2ZMF) [9], a virtual screening was carried out using our in house-chemical library
Summary
Phosphodiesterases are the enzymes responsible for breaking down the cyclic nucleotides cGMP and/or cAMP, which are two of the most important signaling molecules in cells [1]. PDEs are metaloproteins that have two metal ions, magnesium and zinc, involved in catalytic activity They are composed by a highly conserved catalytic domain near the C-terminal, which contains a cyclic nucleotide binding site, as well as by a regulatory one, closed to the N-terminal, which shows more variation among the different PDEs families. The high level of conservation among the 11 PDE families commonly leads to selectivity issues [4] This fact, together with the often wide distribution of these enzymes and the presence of multiple splice variants for everyone, makes the search for specific PDE inhibitors a current challenge. For this reason, new approaches are needed in order to modulate PDE activity, avoiding problems of selectivity. One strategy is to focus on a PDE family with limited isoforms and/or limited tissue distribution, while another feasible approach consists of looking for allosteric
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