TY - JOUR

T1 - Structure-Based Design of Scaffolds Targeting PDE10A by INPHARMA-NMR

AU - Codutti, Luca

AU - Grimaldi, Manuela

AU - Carlomagno, Teresa

N1 - Publisher Copyright: © 2017 American Chemical Society. Copyright: Copyright 2017 Elsevier B.V., All rights reserved.

PY - 2017/6/26

Y1 - 2017/6/26

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85021278405&partnerID=8YFLogxK

U2 - 10.1021/acs.jcim.7b00246

DO - 10.1021/acs.jcim.7b00246

M3 - Article

C2 - 28569061

AN - SCOPUS:85021278405

VL - 57

SP - 1488

EP - 1498

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 6

ER -