2 research outputs found
Identification of Novel Phosphodiesterase-4D Inhibitors Prescreened by Molecular Dynamics-Augmented Modeling and Validated by Bioassay
Phosphodiesterase-4D (PDE4D) has
been proved to be a potential
therapeutic target against strokes. In the present study, a procedure
of integrating pharmacophore, molecular docking, molecular dynamics
(MD) simulations, binding free energy calculations, and finally validation
with bioassay was developed and described to search for novel PDE4D
inhibitors from the SPECS database. Among the 29 compounds selected
by our MD-augmented strategy, 15 hits were found with IC<sub>50</sub> between 1.9 and 50 μM (a hit rate of 52%) and 6 potent hits
showed IC<sub>50</sub> less than 10 μM, which suggested that
MD simulations can explore the intermolecular interactions of PDE4D–inhibitor
complexes more precisely and thus significantly enhanced the hit rate
of this screening. The effective and efficient integrated procedures
described in this study could be readily applied to screening studies
toward other drug targets