Clinical Risk Assessment Of Catechol-o-methyltransferase Inhibitors:Meta-analysis,in Vitro Studies,and Molecular Docking

Objective:Catechol-o-methyltransferase（COMT）is an important phaseâ…¡metabolizing enzyme,which can decompose dopamine through methylation reaction,and is a key target in the treatment of Parkinson’s disease（PD）.COMT inhibitors are often combined with levodopa（L-DOPA）in the treatment of PD patients with exercise complications to prolong the action time of L-DOPA and improve bioavailability.The purpose of this study was to investigate the clinical adverse reactions of opicapone,a new generation of COMT inhibitor,compare the in vitro inhibitory effects and safety of different COMT inhibitors,and conduct molecular docking verification,providing theoretical guidance for further research and development of novel,efficient and low-toxicity COMT inhibitors.Methods:1.Pub Med,Embase,Web of Science,and Cochrane databases are the main databases for searching relevant clinical studies.The end points included any treatment-related adverse events（TEAEs）,serious TEAEs（SAEs）and treatment discontinuation.Meta-analysis was performed using Stata 17.0 software.2.Five COMT inhibitors（catechol,pyrogallol,tolcapone,entacapone,opicapone）were used as research objects.The inhibitory activity of these five inhibitors on COMT were investigated by enzymic reaction kinetics.The selectivity and safety of COMT inhibitors were demonstrated by the IC₅₀ ratio(IC₅₀（S-COMT）/IC₅₀（MB-COMT）of soluble COMT to membrane bound COMT.The X-ray crystal structure of COMT was retrieved and downloaded from RCSB protein database,and the small-molecule structure of COMT inhibitor was obtained from Pub Chem database.Auto Dock software was used to dehydrate and hydrogenate the target protein,add atomic charge,set atomic type,and conduct molecular docking.Results:1.Three RCTs,three RCT extension studies and three open-label studies involving 2177 PD patients were evaluated.In the short-term studies,there were reports of TEAEs with an incidence of≥5%in individuals treated with opicapone50 mg,including dyskinesia（14.1%）,elevated blood creatine phosphokinase levels（8.0%）and urinary tract infection（6.0%）.Any TEAEs,SAEs and treatment discontinuation all occurred at rates of 62.9%,4.8%and 9.3%,respectively.TEAEs with opicapone 50 mg that were reported by more than 5%of patients in long-term studies included dyskinesia（16.1%）,dry mouth（12.1%）,medication effect decreased（12.1%）,PD exacerbated（7.8%）,blood creatine phosphokinase level raised（7.4%）,nausea（6.1%）and insomnia（5.1%）.The incidence of any TEAEs,SAEs and treatment discontinuation were,correspondingly,73.2%,8.7%and 8.4%.2.Catechol and pyrogallol have weak inhibitory effects on COMT.The IC₅₀of tolcapone for daphnetin methylation is 3.3 n M,the IC₅₀ of entacapone for daphnetin methylation is 18.1 n M,and the IC₅₀ of opicapone for daphnetin methylation is 22.1 n M.IC₅₀（S-COMT）/IC₅₀（MB-COMT）results showed that the ratio of opicapone was the largest and that of tolcapone was the smallest.The results of molecular docking showed that tolcapone had the highest docking score with COMT,the possibility of interaction was the highest,and the possibility of interaction was the lowest for opicapone.Conclusion:Meta-analysis showed that opicapone was well tolerated.In vitro inhibition experiments showed that tolcapone,entacapone and opicapone had strong inhibitory activity,and tolcapone had the strongest inhibitory activity.IC₅₀（S-COMT）/IC₅₀（MB-COMT）results showed that opicapone had the best selectivity and the highest safety.The results of molecular docking indicate that the combination of tolcapone and COMT is the highest possibility.The results of molecular docking are consistent with those of in vitro inhibition experiments.