Structural and Computational Analyses of the Unique Interactions of Opicapone in the Binding Pocket of Catechol O -Methyltransferase: A Crystallographic Study and Fragment Molecular Orbital Analyses.

A third-generation inhibitor of catechol -methyltransferase (COMT), opicapone (), has the 3-nitrocatechol scaffold as do the second-generation inhibitors such as entacapone () and tolcapone (), but only can sustainably inhibit COMT activity making it suitable for a once-daily regimen. These improvements should be attributed to the optimized sidechain moiety (oxidopyridyloxadiazolyl group) of substituted at the 5-position of the 3-nitrocatechol ring. We analyzed the role of the sidechain moiety by solving the crystal structures of COMT/-adenosylmethionine (SAM)/Mg/ and COMT/-adenosylhomocysteine (SAH)/Mg/ complexes. Fragment molecular orbital (FMO) calculations elucidated that the dispersion interaction between the sidechains of Leu 198 and Met 201 on the β6β7-loop and the oxidopyridine ring of were unique and important in both complexes. In contrast, the catechol binding site made a remarkable difference in the sidechain conformation of Lys 144. The ε-amino group of Lys 144 was outside of the catalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/ complex. No nitrocatechol inhibitor has ever been reported to make a complex with COMT and SAH. Thus, the conformational change of Lys 144 found in the COMT/SAH/Mg/ complex is the first crystallographic evidence that supports the role of Lys 144 as a catalytic base to take out a proton ion from the reaction site to the outside of the enzyme. The fact that generated a complex with SAH and COMT also suggests that could inhibit COMT twofold, as a typical substrate mimic competitive inhibitor and as a product-inhibition enhancer.