Prospecting for new catechol-O-methyltransferase (COMT) inhibitors as a potential treatment for Parkinson’s disease: a study by molecular dynamics and structure-based virtual screening

Background: The most effective symptomatic treatment of Parkinson’s disease remains the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) B, key metabolic enzymes of L-dopa and dopamine. Objective: This study attempted to discover compounds that exhibit dual inhibition of COMT and MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson’s disease. Methods: Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis. Results: Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM), (+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 = 25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2 µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with specificity for MAO-A. Conclusion: None of the natural products investigated here are dual COMT/MAO-B inhibitors. However, good potency COMT inhibitors have been identified, which may serve as leads for future development of COMT inhibitors.

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Discovery of Novel and Selective Adenosine A2AReceptor Antagonists for Treating Parkinson’s Disease through Comparative Structure-Based Virtual Screening

Journal of Chemical Information and Modeling ◽

10.1021/acs.jcim.7b00188 ◽

2017 ◽

Vol 57 (6) ◽

pp. 1474-1487 ◽

Cited By ~ 21

Author(s):

Sheng Tian ◽

Xu Wang ◽

Linlang Li ◽

Xiaohu Zhang ◽

Youyong Li ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Virtual Screening ◽

Comparative Structure

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COMT Inhibitors: Novel Treatments for Parkinson's Disease

CNS Spectrums ◽

10.1017/s109285290000554x ◽

1998 ◽

Vol 3 (2) ◽

pp. 53-56 ◽

Cited By ~ 1

Author(s):

Charles H. Adler

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Comt Inhibitors ◽

Novel Treatments ◽

New Class ◽

Comt Inhibitor ◽

Duration Of Response

AbstractCatechol-O-methyltransferase (COMT) inhibitors are a new class of medication being developed for the treatment of Parkinson's disease (PD). The enzyme COMT metabolizes levodopa and dopamine, both peripherally and centrally. Coadministration of a COMT inhibitor with levodopa creates an increase in peripheral and central levodopa bioavailability, as well as higher central dopamine concentrations. Because these actions improve the duration of response to levodopa, the COMT inhibitors should prove to be useful adjunctive therapies in PD patients.

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The Treatment of Parkinson's Disease in Older People

Scottish Medical Journal ◽

10.1177/003693309704200511 ◽

1997 ◽

Vol 42 (5) ◽

pp. 147-150 ◽

Cited By ~ 2

Author(s):

C.T.C. Lien ◽

W.J. Mutch

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Older People ◽

Older Patients ◽

Dopamine Agonists ◽

Life Time ◽

Comt Inhibitors ◽

Functional Benefit ◽

Subcutaneous Apomorphine ◽

Variable Combination

Parkinson's disease is characterised by a variable combination of tremor, rigidity, bradykinesia and impaired righting reflexes. The cumulative life-time risk is one in 40. Levodopa remains the single most effective treatment in older patients, and the minimum dose to achieve maxiumu functional benefit should be employed. When fluctuations occur, controlled release preparations and selegiline can improve function. Oral dopamine agonists have a role but the combined side effect profile with levodopa should be monitored. COMT inhibitors have recently become available. Subcutaneous apomorphine can be helpful when “on-off phenomema are marked. The concept of neuroprotection continues to be debated. Surgery is an option for fitter older people but neurotransplantation remains essentially a research tool.

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