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 isoform differs 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 catalytic cavity. In continuation, current work thoroughly presents a 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 enhanced ligand binding affinity in presence of N-terminal domain. Further, atomic level analysis indicated that T-pi and π-π interactions between inhibitors and residues are vital forces that regulate inhibitor association to PDE4B with high affinity. The derived information signifies potential of short range interactions in stabilizing PDE4B-inhibitor complexes, and may be helpful to design and evaluate next-generation selective PDE4B inhibitor.