Evaluation and Optimization of In Silico Designed PDE4B Modulators

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.