(S)-5-Methylmellein Isolated from an Endogenous Lichen Fungus Rosellinia corticium as a Potent Inhibitor of Human Monoamine Oxidase A

In this study, the inhibitory activities against human monoamine oxidases (hMAOs) were evaluated using a library of 195 endogenous lichen fungi from Ukraine. Among them, the extract ELF68 of the endogenous fungus Rosellinia corticium from the lichen Pseudevernia furfuracea (L.) Zopf. exhibited the strongest inhibitory activity against hMAO-A. Using the activity-guided method, (S)-5-methylmellein (5MM) was isolated from the extract and had an IC50 value of 5.31 mu M for hMAO-A with a lower potency for hMAO-B (IC50 = 9.15 mu M). Compound 5MM also moderately inhibited acetylcholinesterase (IC50 = 27.07 mu M) but very weakly inhibited butyrylcholinesterase and beta-secretase. Compound 5MM had a K-i value of 2.45 mu M and was a reversible competitive inhibitor of hMAO-A. A molecular docking study predicted that (S)-5MM showed higher binding affinity for hMAO-A (-6.8 kcal/mol) than hMAO-B (-6.4 kcal/mol). Its isomer, (R)-5MM, exhibited lower binding affinities for hMAO-A (-6.6 kcal/mol) and hMAO-B (-5.2 kcal/mol), compared to (S)-5MM. The S-form interacted with hMAO-A through hydrogen bonding with the Phe208 residue (distance: 1.972 angstrom), while the R-form interacted with the Asn181 residue (2.375 angstrom). The results of an in silico pharmacokinetic analysis indicated that 5MM did not violate Lipinski's five rules and showed high gastrointestinal absorption and blood-brain barrier permeability. These results suggest that 5MM can be considered a candidate in the treatment of neuropsychiatric disorders, such as depression and cardiovascular disease.

Automated summary

This study evaluated the inhibitory activities of lichen fungi against human monoamine oxidases (hMAOs). A compound called (S)-5-methylmellein (5MM) was isolated from an extract and exhibited strong inhibitory activity against hMAO-A. It also showed moderate inhibitory activity against acetylcholinesterase. Molecular docking analysis indicated that 5MM had higher binding affinity for hMAO-A compared to hMAO-B. In silico pharmacokinetic analysis suggests that 5MM has good absorption and permeability properties. These findings suggest that 5MM may be a potential candidate for the treatment of neuropsychiatric disorders.