Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects
Ana M. García,
José Brea,
Alejandro González-García,
Concepción Pérez,
María Isabel Cadavid,
María Isabel Loza,
Ana Martinez,
Carmen Gil
Affiliations
Ana M. García
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
José Brea
Instituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, Spain
Alejandro González-García
Instituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, Spain
Concepción Pérez
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
María Isabel Cadavid
Instituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, Spain
María Isabel Loza
Instituto de Farmacia Industrial, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Universitario Sur s/n, 15782 Santiago de Compostela, Spain
Ana Martinez
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
Carmen Gil
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040 Madrid, Spain
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.
