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 O-methyltransferase(COMT), opicapone (1), has the 3-nitrocatechol scaffoldas do the second-generation inhibitors such as entacapone (2) and tolcapone (3), but only 1 can sustainablyinhibit COMT activity making it suitable for a once-daily regimen.These improvements should be attributed to the optimized sidechainmoiety (oxidopyridyloxadiazolyl group) of 1 substitutedat the 5-position of the 3-nitrocatechol ring. We analyzed the roleof the sidechain moiety by solving the crystal structures of COMT/S-adenosylmethionine (SAM)/Mg/1 and COMT/S-adenosylhomocysteine (SAH)/Mg/1 complexes.Fragment molecular orbital (FMO) calculations elucidated that thedispersion interaction between the sidechains of Leu 198 and Met 201on the & beta;6 & beta;7-loop and the oxidopyridine ring of 1 were unique and important in both complexes. In contrast, the catecholbinding site made a remarkable difference in the sidechain conformationof Lys 144. The & epsilon;-amino group of Lys 144 was outside of thecatalytic pocket and was replaced by a water molecule in the COMT/SAH/Mg/1 complex. No nitrocatechol inhibitor has ever been reportedto make a complex with COMT and SAH. Thus, the conformational changeof Lys 144 found in the COMT/SAH/Mg/1 complex is thefirst crystallographic evidence that supports the role of Lys 144as a catalytic base to take out a proton ion from the reaction siteto the outside of the enzyme. The fact that 1 generateda complex with SAH and COMT also suggests that 1 couldinhibit COMT twofold, as a typical substrate mimic competitive inhibitorand as a product-inhibition enhancer.

Automated summary

The third-generation COMT inhibitor opicapone, with a 3-nitrocatechol scaffold similar to second-generation inhibitors entacapone and tolcapone, has shown sustained COMT inhibition and suitability for once-daily dosing. Crystal structure analysis and FMO calculations revealed the unique and important interaction between the oxidopyridine ring of opicapone and the sidechains of Leu 198 and Met 201. Lys 144 also showed conformational changes in the catechol binding site, and the formation of a complex with SAH and COMT indicates dual inhibition mechanisms of opicapone.