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New role for crinamine as a potent, safe and selective inhibitor of human monoamine oxidase B: In vitro and in silico pharmacology and modeling.

Abstract：

ETHNOPHARMACOLOGICAL RELEVANCE:The development of selective inhibitors of monoamine oxidase B (MAO-B) has been essential in treating Parkinson's disease. However, the apparent hepatotoxicity and drug-drug interactions of current inhibitors accentuate the need for the development of novel pharmacotherapies. Crossyne guttata (L.) D. & U. Müll-Doblies is used frequently by Rastafarian bush doctors to treat alcoholism, a disorder which is also accentuated by MAO. OBJECTIVE:The study sought to isolate, identify and characterise the biologically active constituents of C. guttata based on their ability to inhibit the MAO enzymes. MATERIALS AND METHODS:Column chromatography was used to isolate the biologically active alkaloids of C. guttata. The ability of the alkaloids to inhibit the biotransformation of 4-aminoantipyrine by the MAO enzymes was evaluated in vitro. In silico docking was conducted using AutoDock Vina server while the pharmacokinetic properties of the compounds were evaluated using SwissADME. RESULTS:Chromatographic separation of an ethanolic fraction of C. guttata yielded the alkaloids crinamine 1 and epibuphanisine 2. 1 and 2 along with structurally related alkaloids haemanthamine 3 and haemanthidine 4 were evaluated for their ability to inhibit the action of isozymes of MAO in vitro. Alkaloids effected submicromolar IC50 values against MAO-B, the most potent of which being crinamine 1 (0.014 μM) > haemanthidine 4 (0.017 μM) > epibuphanisine 2 (0.039 μM) > haemanthamine 3 (0.112 μM). Binding energies of the alkaloids correlated well with their inhibitory potential with crinamine displaying the best binding efficacy and binding energy score with MAO-B. DISCUSSION AND CONCLUSION:Crinamine and epibuphanisine exhibited potent and selective inhibitory activity towards MAO-B. After comprehensive in silico investigations encompassing robust molecular docking analysis, the drug-like attributes and safety of the alkaloids suggest the crinamine is a potentially safe drug for human application.

journal_name

J Ethnopharmacol

journal_title

Journal of ethnopharmacology

authors

Naidoo D,Roy A,Slavětínská LP,Chukwujekwu JC,Gupta S,Van Staden J

doi

10.1016/j.jep.2019.112305

subject

Has Abstract

pub_date

2020-02-10 00:00:00

pages

112305

eissn

0378-8741

issn

1872-7573

pii

S0378-8741(19)32037-9

journal_volume

248

pub_type

杂志文章

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New role for crinamine as a potent, safe and selective inhibitor of human monoamine oxidase B: In vitro and in silico pharmacology and modeling.