Investigating the role of N-terminal domain in phosphodiesterase 4B-inhibition by molecular dynamics simulation.

Phosphodiesterase 4B (PDE4B) is a potential therapeutic target for the inflammatory respiratory diseases such as congestive obstructive pulmonary disease (COPD) and asthma. The sequence identity of ∼88% with its isoform PDE4D is the key barrier in developing selective PDE4B inhibitors which may help to overcome associated side effects. Despite high sequence identity, both isoforms differ in few residues present in N-terminal (UCR2) and C-terminal (CR3) involved in catalytic site formation. Previously, we designed and tested specific PDE4B inhibitors considering N-terminal residues as a part of the catalytic cavity. In continuation, current work thoroughly presents an MD simulation-based analysis of N-terminal residues and their role in ligand binding. The various parameters viz. root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF), principal component analysis (PCA), dynamical cross-correlation matrix (DCCM) analysis, secondary structure analysis and residue interaction mapping were investigated to establish rational. Results showed that UCR2 reduced RMSF values for the metal binding pocket (31.5 ± 11 to 13.12 ± 6 Å) and the substrate-binding pocket (38.8 ± 32 to 17.3 ± 11 Å). UCR2 enhanced anti-correlated motion at the active site region that led to the improved ligand-binding affinity of PDE4B from -24.57 ± 3 to -35.54 ± 2 kcal/mol. Further, the atomic-level analysis indicated that T-π and π-π interactions between inhibitors and residues are vital forces that regulate inhibitor association to PDE4B with high affinity. In conclusion, UCR2, the N-terminal domain, embraces the dynamics of PDE4B active site and stabilizes PDE4B inhibitor interactions. Therefore the N-terminal domain needs to be considered while designing next-generation, selective PDE4B-inhibitors as potential anti-inflammatory drugs. Communicated by Ramaswamy H. Sarma.