Phosphodiesterases (PDE) hydrolyze both cyclic AMP and GMP (cAMP/cGMP) and are responsible for the regulation of their levels in a multitude of cellular functions. PDE10A is expressed in the brain and is a validated target for both schizophrenia and Huntington disease. Here, we address the identification of novel chemical scaffolds that may bind PDE10A via structure-based drug design. For this task, we use INPHARMA, an NMR-based method that measures protein-mediated interligand NOEs between pairs of weakly, competitively binding ligands. INPHARMA is applied to a combination of four chemically diverse PDE10A binding fragments, with the aim of merging their pharmacophoric features into a larger, tighter binding molecule. All four ligands bind the PDE10A cAMP binding domain with affinity in the micromolar range. The application of INPHARMA to identify the correct docking poses of these ligands is challenging due to the nature of the binding pocket and the high content of water-mediated intermolecular contacts. Nevertheless, ensemble docking in the presence of conserved water molecules generates docking poses that are in agreement with all sets of INPHARMA data. These poses are used to build a pharmacophore model with which we search the ZINC database.