3D-QSAR pharmacophore modeling and in silico screening of new Bcl-xl inhibitors.
Bcl-2 proteins family members play several roles in tumoral proliferation: they inhibit proapoptotic activity during oncogenesis, support tumor cells survival, induce chemoresistance. The discovery of new small inhibitors of Bcl-xl represents a new frontier for cancer treatment. In this study, a 3D-QSAR pharmacophore model was developed, based on 42 biarylacylsulfonamides, and used to understand the structural factors affecting the inhibitory potency of these derivatives. Aromatic, negative charge, and hydrogen bond acceptor effects contribute to the inhibitory activity. The model was then employed as 3D search query to screen ZINC drug-like database in order to select new scaffolds. Finally six hits were identified. Docking study evidenced the capability of these compounds to interact with Bcl-xl receptor, and they were selected for further in vitro and in vivo assay studies.
Almerico
Anna Maria
AM
Dipartimento Farmacochimico, Tossicologico e Biologico, Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy. almerico@unipa.it
Tutone
Marco
M
Lauria
Antonino
A
D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
D051020:bcl-X Protein