N-(thiazol-2-yl)-2-thiophene carboxamide derivatives as Abl inhibitors identified by a pharmacophore-based database screening of commercially available compounds.
Suggestions derived from a previous ligand-based ligand design approach and docking calculations aimed at finding compound with affinity toward Abl and molecular scaffolds previously untested as Abl inhibitors, led to the identification of commercially available N-(thiazol-2-yl)-2-thiophene carboxamide derivatives with affinity in a cell-free assay up to low nanomolar concentrations, significantly enhanced with respect to that of their parent compounds previously reported. In particular, among compounds of the Asinex database, molecular docking simulations guided the choice of high-affinity ligands, predicting their binding mode and their interaction pattern with the Abl catalytic binding site. Moreover, affinity of the new compounds was also rationalized in terms of their interactions with the enzyme.
Manetti
Fabrizio
F
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100, Siena, Italy.
Falchi
Federico
F
Crespan
Emmanuele
E
Schenone
Silvia
S
Maga
Giovanni
G
Botta
Maurizio
M
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D054852:Small Molecule Libraries / Q000032:analysis; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000577:Amides; D008024:Ligands; D054852:Small Molecule Libraries; D013844:Thiazoles; D013876:Thiophenes; D016315:Proto-Oncogene Proteins c-abl