Synthesis, biological evaluation, and three-dimensional in silico pharmacophore model for sigma(1) receptor ligands based on a series of substituted benzo[d]oxazol-2(3H)-one derivatives.
Novel benzo[d]oxazol-2(3H)-one derivatives were designed and synthesized, and their affinities against sigma receptors were evaluated. On the basis of 31 compounds, a three-dimensional pharmacophore model for the sigma(1) receptor binding site was developed using the Catalyst 4.9 software package. The best 3D pharmacophore hypothesis, consisting of one positive ionizable, one hydrogen bond acceptor, two hydrophobic aromatic, and one hydrophobic features provided a 3D-QSAR model with a correlation coefficient of 0.89. The best hypothesis was also validated by three independent methods, i.e., the Fisher randomization test included in the CatScramble functionality of Catalyst, the leave-one-out test, and activity prediction of an additional test set. The achieved results will allow researchers to use this 3D pharmacophore model for the design and synthesis of a second generation of high affinity sigma(1) ligands, as well as to discover other lead compounds for this class of receptors.
Zampieri
Daniele
D
Department of Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
Mamolo
Maria Grazia
MG
Laurini
Erik
E
Florio
Chiara
C
Zanette
Caterina
C
Fermeglia
Maurizio
M
Posocco
Paola
P
Paneni
Maria Silvia
MS
Pricl
Sabrina
S
Vio
Luciano
L
D000818:Animals; D001554:Benzene / Q000737:chemistry*; D019295:Computational Biology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D001554:Benzene; D008024:Ligands; D010080:Oxazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor