Cyclic nucleotide phosphodiesterase type 5 (PDE5), exclusively specific for the cyclic guanosine monophosphate (cGMP), is an important drug target for the treatment of erectile dysfunction and pulmonary arterial hypertension (PAH). Although many PDE5 inhibitors have been approved, such as sildenafil, vardenafil, tadalafil and so on, extensive studies have reported some side effects, such as vision disturbance and hearing loss as a result of the amino acid sequence and the secondary structural similarity of other PDEs to the catalytic domain of PDE5. In this study, multiple docking strategies, molecular dynamics (MD) simulations, free energy calculations and decomposition were employed to explore the structural determinants of PDE5 with a series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives. First, reliable docking results were obtained using quantum mechanics/molecular mechanics (QM/MM) docking. Then, MD simulations and MM/GBSA free energy calculations were used to explore the dynamic binding process and characterize the binding modes of the inhibitors with different activities. The predicted binding free energies are in good agreement with the experimental data, and the MM/GBSA free energy decomposition analysis sheds light on the importance of hydrogen bonds with Gln817, π-π stacks against Phe820 and hydrophobic residues for the PDE5 binding of the studied inhibitors. The structural and energetic insights obtained here are useful for understanding the molecular mechanism of ligand binding and designing novel potent and selective PDE5 inhibitors with new scaffolds.
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