Dual-Target Compounds Could Lead to Single and More Effective Therapy for Parkinson’s, Study Reports

Pharmacologic compounds that can act on two target molecules show promise as potential therapies for Parkinson’s disease, according to a study that details a new way of finding such compounds.

The study, “Docking screens for dual inhibitors of disparate drug targets for Parkinson’s disease,” was published in the Journal of Medicinal Chemistry.

Neurodegenerative diseases such as Parkinson’s are complex and affect multiple molecules, and treating them often requires modulating several targets.

Developing a single therapy that can act on several biological targets is, for this reason, a major goal in treating these disorders, because such a therapy is of greater efficacy  compared to single-target therapies, and more likely to avoid the side effects associated with a combination therapy.

A frequently used method to design compounds that specifically bind to target molecules is known as structure-based drug design or molecular docking. The method uses a three-dimensional structure of a target molecule to predict the “best-fit” orientation of a compound that stably binds to its target.

However, the rational design of compounds that interact with several targets is very challenging, and the vast majority of known multi-target drugs has been discovered by serendipity and mainly involve targets that are either closely related or recognize similar molecules.

Now, researchers used structure-based virtual screening to find potential therapeutic compounds that would simultaneously target and suppress two unrelated molecules associated with Parkinson’s disease — A2A adenosine receptor (A2AAR) and monoamine oxidase B enzyme (MAO-B).

A compound that could target both A2AAR and MAO-B would potentially improve motor function and better protect nerve cells (related to A2AAR suppression), and increase dopamine levels – a key chemical messenger found in reduced levels in Parkinson’s patients — due to MAO-B suppression.

Virtual screening of a commercial chemical library containing 5.4 million compounds spotted 24 compounds with elevated binding potential to both A2AAR and MAO-B.

Experiments showed that 14 of these compounds bound to at least one of the molecules, and four compounds targeted both molecules. Two of them were considered to have the best profile for the dual binding, and functional tests confirmed they could suppress both A2AAR and MAO-B.

The two compounds were able to induce protective effects in dopamine-producing nerve cells grown in the lab, which are used as a Parkinson’s model.

These compounds “provide excellent starting points for development of dual-target A2AAR/MAO-B leads that could be evaluated in vivo for antiparkinson activity,” the researchers wrote.

Despite the structural differences between A2AAR and MAO-B, structure-based virtual screening was still able to identify effective dual-target compounds, supporting its use as a tool for identifying multi-target compounds for disparate targets.

“Our results demonstrate that molecular docking screening can guide discovery of ligands with specific polypharmacological profiles [that act on multiple targets], which can contribute to development of drugs against complex diseases with improved efficacy and less side effects,” the researchers concluded.