Cheminformatics and virtual screening studies of COMT inhibitors as potential Parkinson’s disease therapeutics

ABSTRACT

Introduction: Parkinson’s Disease (PD) is a neurodegenerative central nervous system (CNS) disorder characterized by dopaminergic neuron degeneration with consequent reduction in striatal dopamine (DA) levels that leads to motor symptoms. Catechol-O-methyltransferase (COMT, E.C 2.1.1.6) inactivates dopamine and other substrates bearing catechol through the methylation of a hydroxyl group. COMT inhibition can block metabolism of catecholamines including DA. Since the increase in DA bioavailability is dependent on the inhibition of DA metabolism at the periphery, the development of COMT inhibitors as adjuvants to levodopa/aromatic amino acid decarboxylase (AADC) inhibitor treatment improves the clinical benefits of PD symptomatic treatment significantly.

Areas covered: This review focuses on the contribution of computational studies to develop novel COMT inhibitors as therapeutics of Parkinson’s disease with substantially improved efficacy.

Expert opinion: The increasing use of in silico methods and the development of new chemoinformatic tools in combination with the knowledge gained from the development of different inhibitors studied both in silico, in vitro and in vivo, could help solve a number of issues related to the shortcomings of currently marketed treatments. They can also aid to open new avenues for centrally acting COMT inhibitors, and perhaps irreversible inhibitors, to be tested for PD and other neurological diseases.

KEYWORDS:

• Catechol-O-methyltransferase
• cheminformatics
• COMT inhibitors
• drug design
• Parkinson’s disease

Article Highlights

• COMT inhibitors have an important role as adjuvants in the Parkinson’s disease treatment by inactivating dopamine and the drug levodopa as well.

• Integrating approach of molecular modeling studies coupled with in vitro and in vivo data from a variety of developed inhibitors provides an opportunity to develop novel safe and efficacious COMT inhibitors.

• Toxicity is a major concern of many COMT inhibitors developed (marketed and experimental). Flavonoids and bisubstrate inhibitors that lack the nitro group may provide molecules with less toxicity.

• Centrally acting COMT inhibition needs to be addressed by synthesizing molecules that are permeable to BBB while retaining other essential properties.

• COMT inhibitors will continue to be a major drug class for PD, and potential other neurological conditions, and hence research on the development of such improved molecules should continue with the aid of computer tools.

This box summarizes key points contained in the article.

Declaration of interest

A Afantitis is an employee of NovaMechanics Ltd, Nicosia, Cyprus. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewers Disclosures

One referee has served as an advisor to ORION, Roche, BIAL Pharmaceuticals in the past. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

A Afantitis and L Zacharia acknowledge support by the ENTERPRISES/0916/142 project, which was co-funded by the European Regional Development Fund and the Republic of Cyprus through the Research and Innnovation Foundation.