Structural exploration of selected C6 and C7-substituted coumarin isomers as selective MAO-B inhibitors

Abstract

Monoamine Oxidase B is considered a successful target for developing antiparkinsonian drugs. Due to the side effects of current MAO-B inhibitors, there’s an urgent need for novel potent and highly selective MAO-B inhibitors. A recent study has shown that coumarins tend to be more selective towards MAO-B than MAO-A when connected to a hex-5-ynyloxy chain at position 6 in contrast to their C7-isomers. The present study describes the mode of interaction of the C6 and C7-substituted coumarin isomers characterized by their difference in selectivity towards MAO-B through molecular docking and molecular dynamics simulations in an effort to elucidate the structural components and molecular interactions that may be responsible for MAO-B selectivity. Three isomeric coumarin pairs connected to ether chain at position 6 or 7 were taken from the literature and modelled according to their IUPAC nomenclature. Molecular docking study revealed one π- π stacking interaction with Tyr-326 in common between the selective coumarin C6-isomers. Resulting complexes of one isomeric coumarin pair that displayed the highest selectivity shift towards MAO-B were subject to 100 ns molecular dynamics simulations study to analyze the stability of the docked complexes. Molecular dynamics revealed that the C7-isomer is relatively stable in both MAO isoforms through the simulation duration, whereas the C6-isomer deemed unstable for MAO-A which may be due to the bulky Phe-208 residue in MAO-A. Our results might be applied for further development and optimization of coumarin derivatives into a successful drug against Parkinson’s disease.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coumarin
• selectivity
• monoamine oxidase A
• monoamine oxidase B
• molecular docking
• Parkinson’s disease
• ADME
• drug likeness
• Lipinski’s rule of five
• molecular dynamics simulation

Acknowledgments

We would like to thank Francisco Javier Luque Garriga, Professor in the Department of Chemical Physics, University of Barcelona, Spain, for his assistance. His contribution is sincerely appreciated and gratefully acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.