Potent and Selective Inhibitors of Human Monoamine Oxidase A from an Endogenous Lichen Fungus Diaporthe mahothocarpus.

Sang-Jip Nam,Hoon Kim,Daeui Park,Sungbo Hwang,Myung-Gyun Kang,Prima F. Hillman,Jong-Eun Park,Geum Seok Jeong

doi:10.3390/jof7100876

Abstract

Using 126 endogenous lichen fungus (ELF) extracts, inhibitory activities against monoamine oxidases (MAOs) and cholinesterases (ChEs) were evaluated. Among them, extract ELF29 of the endogenous fungus Diaporthe mahothocarpus of the lichen Cladonia symphycarpia showed the highest inhibitory activity against hMAO-A. Compounds alternariol (AT), 5′-hydroxy-alternariol (HAT), and mycoepoxydiene (MED), isolated from the extract, had potent inhibitory activities against hMAO-A with IC50 values of 0.020, 0.31, and 8.68 µM, respectively. AT, HAT, and MED are reversible competitive inhibitors of hMAO-A with Ki values of 0.0075, 0.116, and 3.76 µM, respectively. The molecular docking studies suggested that AT, HAT, and MED had higher binding affinities for hMAO-A (−9.1, −6.9, and −5.6 kcal/mol, respectively) than for hMAO-B (−6.3, −5.2, and −3.7 kcal/mol, respectively). The relative tight binding might result from a hydrogen bond interaction of the three compounds with a Tyr444 residue in hMAO-A, whereas no hydrogen bond interaction was proposed in hMAO-B. In silico pharmacokinetics, the three compounds showed high gastrointestinal absorption without violating Lipinski’s five rules, but only MED showed high probability to cross the blood–brain barrier. These results suggest that AT, HAT, and MED are candidates for treating neuropsychiatric disorders, such as depression and cardiovascular disease.

Highlights

Lichens, called the clothes of the earth, are complex organisms in which green or blue-green algae have a symbiotic relationship with fungi
We reported that 5-hydroxy-2-methyl-chroman-4-one was isolated from an endogenous lichen fungus (ELF) extract, and it had selective inhibition of hMAOB [6]
ELF21, ELF24, ELF29, ELF93, and ELF114 were potent against hMAO-A

Summary

Introduction

Lichens, called the clothes of the earth, are complex organisms in which green or blue-green algae have a symbiotic relationship with fungi. Lichens are found in various environments, from temperate regions and tropical rainforests to extremely cold regions, such as deserts, tundra, and volcanoes; it is predicted that the materials they produce help them adapt to the environment [2]. Their primary and secondary metabolites exhibit diverse biological activities, such as antibiotic, antifungal, antiviral, anti-inflammatory, analgesic, antipyretic, antiproliferative, cytotoxic, and antioxidant effects [3,4]. Alzheimer disease (AD), which can cause 60–70% of dementia, is a neurodegenerative disease that progresses slowly and gets worse.

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