The design and identification of novel Protein Kinase inhibitors using the naturally occurring Staurosporine scaffold as a lead

Abstract

Staurosporine is a naturally occurring alkaloid isolated from the bacterium Streptomyces staurosporesa. It inhibits the protein kinases class of enzymes (including protein kinase C) inducing cell apoptosis and thus resulting in it having potential anti tumour activity. Recent studies showed that staurosporine had high affinity for the protein kinase C receptor, however lacked selectivity resulting in a wide adverse effect profile. Thus, this study targets the protein kinase C receptor for the generation of novel structures capable of its inhibition using staurosporine as template molecule. This study has yielded two molecular cohorts, one from each approach. These were filtered for Lipinski Rule compliance and segregated into families of pharmacophoric similarity and ranked in order of affinity. The molecules with the best ligand binding affinities were generated using the de novo approach. The best molecule from the de novo approach had an affinity of 10, while the best molecule from the virtual screening approach had an affinity of 9.65. This study was valuable in demonstrating that the staurosporine scaffold was suitable for the identification and design of high affinity structures capable of modulating the protein kinase C receptor through two distinct approaches- de novo design and virtual screening. The affinities of the optimal molecules exceeded that of stautosporine, and these molecules will be proposed for further study. Specifically, their enhanced molecular interactions will be explained from an atomic perspective, and also through molecular dynamic simulation studies.