The Choice of Atomic Charges Calculation Scheme in 3D-QSAR Modelling of GSK-3β Inhibition by Paullones

摘要

Paullones (7,12-dihydroindolo[3,2-d][1]benza-zepine-6(5H)-ones, 1) were identified as novel anti-proliferative compounds during the high-throughput screening campaign performed at the National Cancer Institute, USA (NCI) in 1999 [1]. These compounds show inhibition of cyclin-dependent kinases (CDK) [1-3] and glycogen synthase kinase 3β (GSK-3P) [3]. Inhibition of GSK-3β is specially interesting because, in contrast to cyclin-dependent kinases, it is involved not only in oncogenic pathways but also in insulin metabolism [4] and in memory formation [5]. GSK-3β inhibitors were proposed as drugs for the treatment of type 2 diabetes, Alzheimer's disease, and other socially significant diseases, such as malaria and sleeping sickness [6]. It is interesting to develop new potent paullone inhibitors of GSK-3β with suitable pharma-cokinetic properties for targeted treatment of diseases mediated by this kinase.