Molecular Modelling and Synthesis of PDE4 Inhibitors

The phosphodiesterase 4 (PDE4) enzyme, which is responsible for hydrolyzing cAMP in immune cells and the central nervous system, is one of eleven PDE families ranging from PDE1 to PDE11. PDE4 is implicated in a number of conditions such as psoriasis, plaque psoriasis, chronic obstructive pulmonary disease, schizophrenia, and depression, making it a promising target for pharmaceutical development. Current PDE4 inhibitors on the market such as Otezla, Crisaborole, and Daxas target inflammatory diseases like psoriasis, atopic dermatitis, and COPD. Ligands which act as inhibitors of PDE4 and have high binding affinity to the active sites, thereby increasing levels of cAMP in immune cells, are being investigated to treat patients with these conditions. Through molecular docking experiments, a common method used in drug design, we bound different proposed benzothiazole inhibitors to the binding site of a crystallized PDE4 structure. Using the results of the experiments conducted with AutoDockTools, we were able to determine preferred poses of the ligands as well as their predicted binding affinity to PDE4. In addition, we performed the synthesis of benzothiazoles by Hugerschoff’s reaction at different times and temperatures to optimize the yield. The resulting compounds were characterized by TLC and NMR