Uncovering the selectivity mechanism of PDE4B and PDE4D through computational investigations

It is a promising strategy that inhibiting Phosphodiesterase-4 (PDE4) proteins for treating a variety of diseases including central nervous system disorders, inflammation, and chronic obstructive pulmonary disease (COPD). However, the unwanted side effects would be appeared by using non-selective inhibition of PDE4 isoforms, especially inhibiting PDE4B and PDE4D simultaneously. So the compound T2525 and ZINC33106106 (ZINC), which were the PDE4B and PDE4D selective inhibitors respectively, were selected. The interactions between inhibitor with its targeted protein (PDE4B and PDE4D) were investigated using molecular docking, molecular dynamic simulation, and calculation of the MM-GBSA. The results showed that PDE4B and PDE4D shared high sequence homology in their active sites. While there were some differences from key residues, such as PHE506PDE4D, PHE538PDE4D, PHE599PDE4D, and PHE446PDE4B, TYR403PDE4B, that determined the feasibility of selective inhibitors of PDE4B and PDE4D. These findings would provide the new sites of targeted proteins theoretically for further structural optimization of selective inhibitors between PDE4B and PDE4D.