Structural insights into the lead identification of sub-type selective PDE4B inhibitors from plant bioactive molecule analogues

Phosphodiesterase-4B (PDE4B), a sub-type of PDE4, is highly expressed in the brain and associated with schizophrenia, neuroinflammation, and cognition. A selective inhibitor of PDE4B is anticipated to be a promising drug candidate for addressing related disorders. It is crucial to identify the factors that influence inhibitor specificity and the binding process to design PDE4B inhibitors with high efficiency and specificity. This includes investigating the role of various essential residues within the active site pockets (Q, M, and S). Therefore, molecular docking and atomistic molecular dynamics simulations were performed to assess the inhibitory potential of benzosuberene-sulfone (BSS) molecules against PDE4B compared to the standard drug roflumilast. The S6 and S10 BSS analogues formed stable complexes and exhibited lower binding free energy than the standard molecule. Additionally, it was observed that the S6 and S10 accommodated well inside the Q and S-pockets of PDE4B. The study also highlighted the importance of amino acid residue Met-431 (Q-pocket residue) to achieve sub-type selectivity. Furthermore, the pulling simulations revealed that the S6 molecule required the highest force to unbind from the binding cavity and showed key interactions with Met-431 during the unbinding process. The umbrella sampling simulations revealed binding free energies of -69.09 ± 1.37 kJ/mol for S6 and -55.11 ± 1.69 kJ/mol for roflumilast, underscoring a higher affinity of S6 for PDE4B. This study presented compelling evidences that the S6 molecule could be a promising lead for the selective inhibition of PDE4B.