Details
| Original language | English |
|---|---|
| Pages (from-to) | 1488-1498 |
| Number of pages | 11 |
| Journal | Journal of Chemical Information and Modeling |
| Volume | 57 |
| Issue number | 6 |
| Early online date | 12 Jun 2017 |
| Publication status | Published - 26 Jun 2017 |
Abstract
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.
ASJC Scopus subject areas
- Chemistry(all)
- General Chemistry
- Chemical Engineering(all)
- General Chemical Engineering
- Computer Science(all)
- Computer Science Applications
- Social Sciences(all)
- Library and Information Sciences
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In: Journal of Chemical Information and Modeling, Vol. 57, No. 6, 26.06.2017, p. 1488-1498.
Research output: Contribution to journal › Article › Research › peer review
}
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 -