CODES, a novel procedure for ligand-based virtual screening: PDE7 inhibitors as an application example.
Phosphodiesterase (PDE) 7 is a high affinity cAMP-specific PDE whose functional role in T-cells has been the subject of some controversy. Recent findings on tissue distribution, however, support the hypothesis that PDE7 could be a good target for the treatment of airway diseases, T-cell related diseases or central nervous system (CNS) disorders. Therefore, the identification of selective inhibitors targeted against PDE7 enzyme has become an attractive area of research. We report here the first use of the descriptors generated by the CODES program for ligand-based virtual screening. This program codifies molecules from a topological point of view and the generated descriptors are related to the chemical nature of the atoms, the atomic bonds and the connectivity with the rest of the molecule. They are also able to distinguish among stereoisomers. By using this approach, 173 compounds were codified, and their similarity with the reference compound was analysed. Based on the analysis, new potential PDE7 inhibitors have been identified, synthesized and biologically evaluated confirming that CODES descriptors are valid for ligand-based virtual screening and provided new lead compounds for further optimization as potent and selective PDE7 inhibitors.
Castro
Ana
A
Instituto de Química Médica (CSIC), Juan de la Cierva 3, Madrid, Spain. acastro@neuropharma.es
Jerez
María José
MJ
Gil
Carmen
C
Calderón
Félix
F
Doménech
Teresa
T
Nueda
Arsenio
A
Martínez
Ana
A
D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000187:drug effects*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet
D008024:Ligands; D010726:Phosphodiesterase Inhibitors; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7