Tolcapone, drug for Parkinson's Disease Couple with Levodopa and Decarboxylase inhibitor

1. An TranVo
SDSU Chem 763
Spring 2017

2. Overview:
• Parkinson’s Disease
• Background Tolcapone: COMT inhibitor drug
• COMT: target enzyme
• Mechanism in action
• Interactions between Tolcapone and COMT
• Detection

3. Parkinson’s Disease (PD):
• A neurological disorder: low dopamine level in
Central Nerve System (CNS).
• Dopamine is a neurotransmitter that helps nerve
cells communicate to controls balance and muscle
movement

4. Tolcapone:
• COMT inhibitor (IC50 = 36 nM)
• FDA approved in 1998, but issued a black box warning in 2009
due to the risk of liver failure that can lead to death.
• Combine with Levodopa/Decarboxylase inhibitor therapy.
• Withdrawn if :
 No improvement in dopamine level in the brain within 3
weeks
 SGPT/ALT or SGOT/AST levels exceed 2 times the
upper limit of normal
 Clinical signs and symptoms suggest the onset of hepatic
dysfunction

5. Tolcapone: Lipinski’s Rule of 5
• Molecular mass:
273.244 g/mol < 500 g/mol ✔
• H bond donors: 2 < 5 ✔
• H bond acceptors: 5 <10 ✔
• LogP: 4 < 5 ✔

6. Catechol-O-methyltransferase (COMT):
• One single domain withα-
helices arranged around a
central mixed β-sheet
• Catalytic site: binds one
Mg2+ and the catechol
substrate
• SAM-binding site
DOI:10.2210/pdb3s68/pdb

7. Catechol-O-methyltransferase (COMT):
• Catalyzes the methylation of dopamine or COMT inhibitor
by using S-adenosyl-L-methionine (SAM) as a methyl donor
and yielding the O-methylated catechol and S-adenosyl-L-
homocysteine (SAH)

8. Mechanism in action:
• Tolcapone is used with Levodopa and Decarboxylase
inhibitor.
• Levodopa (L-DOPA): dopamine supplementation
• Levodopa is converted to Dopamine by the aromatic l-
amino acid decarboxylase (AADC)

9. Mechanism in action:
• Only approximately 1% of
an oral dose of levodopa
reaches the brain and
converted into Dopamine
• Levodopa is extensively
converted into dopamine by
Decarboxylase and into 3-
O-methyldopa (3-OMD) by
COMT enzyme in GI track,
liver and kidney; also in the
brain

10. Mechanism in action:
• Levodopa with an AADC
inhibitor to prevent its
conversion to dopamine in
peripheral tissues: only 5–
10% of an oral dose of
levodopa reaches the brain
• Tolcapone prevent the
degradation of Levodopa
and Dopamine
• Increases the relative
bioavailability of levodopa
by approximately twofold

11. Tolcapone: in hydrophobic pocket of COMT
DOI:10.2210/pdb3s68/pbd

12. Tolcapone: H bonds with COMT
• Asp 141 (2.5Å )
• Lys 144 (1.9Å and
2.6Å)
• Asn 170 (both 2.1Å )
• Glu 199 (1.8Å )
DOI:10.2210/pdb3s68/pb

13. Tolcapone: interact with Mg2+ in COMT
• Mg2+ ion is an anchor of Tolcapone in a
catalytic position
DOI:10.2210/pdb3s68/pbd

14. Tolcapone: interact with SAM in COMT
• 1 (-OH) of Tolcapone is positioned in proximity to
the activated methyl group of SAM
DOI:10.2210/pdb3s68/pbd

15. Conformational changes of COMT:
DOI:10.2210/pdb4pyl/pbd
In SAM binding site

16. Conformational changes of COMT:
DOI:10.2210/pdb4pyl/pbd
In SAM binding site

17. Conformational changes of COMT:
DOI:10.2210/pdb4pyl/pbd
In Catalytic site

18. Conformational changes of COMT:
DOI:10.2210/pdb4pyl/pbd
In Catalytic site
K187
D188

19. Conformational changes of COMT:
DOI:10.2210/pdb4pyl/pbd
In Catalytic site

20. Metabolites of Tolcapone:
• Tolcapone is almost completely
metabolized prior to excretion
• 0.5% of dose found unchanged in
urine
• Tolcapone metabolites in urine
(60%) and in feces (40%)
• The primary metabolic pathways
is glucuronidation, also
methylation, oxidative
hydroxylation and reduction
reactions

21. Tolcapone: Detection

22. Tolcapone: Detection

23. Tolcapone: Detection by MS

24. Conclusion:
• Tolcapone combination with Levodopa/AADC
inhibitor: increase the amount of levodopa reaching the
brain, by protecting its O-methylation in the periphery
• High affinity and contribute to COMT conformational
changes
• Tolcapone is completely metabolized prior to excretion:
high risk of liver failure.
• Tolcapone and its metabolites can be detected by
different techniques.

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