Claire Shoemake

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 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 development 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.

Cyclic nucleotide phosphodiesterase 4 (PDE4) catalyses the hydrolysis of 3’,5’-cyclic AMP to 5’-AMP. Inhibition of this enzyme preserves high intracellular levels of cAMP which in turn causes suppression of TNF-α and other pro-inflammatory cytokines. It also promotes the expression of anti-inflammatory mediators. The design of small molecule inhibitors selective for PDE4B subtype is considered relevant owing to the fact that this could lead to the identification of potent anti-inflammatory agents with a low side effect profile. In vitro evidence was indicative of the fact that a synthesized analog series of xanthine derivatives were PDE4B inhibitors. This in silico study consequently sought to model the xanthine scaffold within the PDE4B Ligand Binding Pocket (PDE4B_LBP) in order to understand the critical interactions forged by this scaffold and the amino acids lining the PDE4B_LBP and to use this information to model novel high affinity selective PDE4B inhibitors. The results obtained from the study were structurally insightful. The xanthine scaffold was deemed suitable for the design of PDE4B modulators. It was however determined that slight modifications of this scaffold could impart greater selectivity for the 4B cyclic nucleotide phosphodiesterase subtype. The modified xanthine scaffold was consequently further optimized and a series of high affinity molecules with varying physiochemical properties was identified.