Origin for the PDE4B-specific inhibitor selectivity
The origin of the selectivity of PDE4B inhibitors were investigated by using molecular dynamics simulations and binding free energy calculations.Firstly,the impact of simulation time,solute dielectric constants,ligand charge schemes,and binding free energy calculation methods on the accuracy of the predicted binding free energy were investigated.Optimal simulation conditions were identified as follows:a simulation time of 40～50 ns,a solute dielectric constant(ε)of 2,the employment of the MM/GBSA method,and utilization of the RESP ligand charge calculation scheme.Subsequently,the interactions between inhibitor A33 and PDE4B/PDE4D were analyzed through energy decomposition.It was found that Ile410,Gln443,Phe446,and Phe506 on the PDE4B enzyme contributed significantly to the selective recognition of inhibitors.Finally,the effect of Leu502 residue from the PDE4B CR3 helix on A33 selectivity was explored through site mutation method.The present work provided valuable insight on the structure-activity relationship for designing highly active and selective PDE4B inhibitors.
phosphodiesterase 4B inhibitorsmolecular dynamics simulationbinding free energy calculationenergy decompositionPDE4B/PDE4D selectivity
万方数据
维普
