[Molecular study of mechanisms of action of cilostazol on certain families of phosphodiesterases].

Abstract

Objective: The purpose of the study was to examine the effect of cilostazol on isoforms of targets of phosphodiesterase 3 and phosphodiesterase 5 by means of molecular modeling.

Material and methods: Inhibition of phosphodiesterases (PDEs) was studied by means of molecular docking using software Maestro Schrodinger Inc. The structure of all mentioned proteins was taken from the Protein Data Bank (PDB): 7L27-PDE3A, 1JOS-PDE3B, 4MD6-PDE5. The structures of cilostazol and vardenafil ligands were obtained from the PubChem database. The Glide Docking SP mode was used to determine the best pose of the ligand in the supramolecular complex PDE-ligand with the function of minimal assessment of energy. The structures of PDEs were taken from protein database. Each molecule of PDE was prepared before docking using the Protein Preparation Wizard module. The ligand geometry was optimized using the force field MMF4 in the software package of molecular dynamics GROMACS. The active center of enzymes was considered rigid, with the change of torsion angles being allowed for cilostazol. The results were visualized using the function Ligand Interaction in the Maestro module. The inhibition constant (Ki) was obtained from the binding energy (ΔG) using the formula: Ki=exp (ΔG/RT), where R is the universal gas constant (1.985 × 10³ kcal · mol 1 · K 1) and T is the temperature (298.15 К).

Results: Cilostazol possesses higher affinity to isoform of PDE3A (Ki=54 nM) as compared with PDE3B (Ki=1.13 μM) based on the findings of the performed molecular docking. Also, cilostazol can inhibit PDE5 in therapeutic doses (Ki=10 μM).

Conclusion: Cilostazol-mediated inhibition of the isoform PDE3A to a greater degree than PDE3B explains a low incidence of side effects from the side of PDE3B inhibition in clinical practice. Cilostazol may also inhibit PDE5 at therapeutic doses (Ki=10 μM), in which connection it may have an additional therapeutic effect in treatment of intermittent claudication, diabetes mellitus and its complications, especially neuropathy.