Discovery of Monoamine Oxidase A Inhibitors Derived from in silico Docking

Abstract

Although more than 20,000 papers concerning monoamine oxidase (MAO) have been reported in PubMed since the 1950s, over 300 papers are still being published every year on this topic. This indicates the importance of MAO, which was discovered by Mary Hare-Bernheim in 1928. 1Two isoforms of MAO have been identified based on the selectivity to their substrates and inhibitors; they are called MAOA and MAOB. While the former shows a high affinity for serotonin and norepinephrine, the latter has a high affinity for β-phenylethylamine. Likewise, MAOA is selectively inhibited by clorgyline and MAOB by selegiline. 2MAOA and MAOB are encoded from different genes that are located in the human X chromosome.3 They are activated by different transcription factors; 4 thus, the expressions of the two proteins are localized: the ratio of MAOA to MAOB is 1:3 in the human brain, 1:1 in the liver, and 4:1 in the intestine.5,6 MAO acts on monoamines, but it does not metabolize diamines. It metabolizes monoamine to aldehyde, which is then oxidized to carboxylic acid by aldehyde dehydrogenase. During this oxidation, MAO requires flavin adenine dinucleotide (FAD), which becomes FADH 2 . The oxidation of FADH 2 is achieved by the production of hydrogen peroxide from oxygen and protons. Consequently, catabolism of MAO produces hydrogen peroxide. Especially, MAOA oxidizes and degrades serotonin which modulates neuropsychiatric function and dysfunction. 7,8 In addition, MAOA has effects on several psychiatric conditions such as anxiety, mood, and impulsivity, and is implicated in several psychiatric illnesses and elevated in depressive disorder. 9,10

(E)-1-(3,5-Dimethoxyphenyl)-3-(3-methoxyphenyl)prop-2-en-1-one

“…They have shown diverse biological activities including anti-cancer (Shenvi et al 2013), anti-microbial (Sharma et al 2012), anti-diabetic (Hsieh et al 2012) and anti-inflammatory (Sashidhara et al 2011). As a part of our studies on the substituent effects of chalcones on structures and biological activities (Jo et al, 2012;Hwang et al, 2011), the title compound was synthesized and its crystal structure was determined.…”

Quercetin and Related Chromenone Derivatives as Monoamine Oxidase Inhibitors: Targeting Neurological and Mental Disorders

“…Moreover Greeson and coauthors also discussed the pharmacological, toxicological, and clinical aspects on MAO inhibitory action of St. John’s wort ( Hypericum perforatum ) [62]. Design of the 3-(4-methoxyphenyl)-1H-benzo[f]chromen-1-one (Figure 15) was carried out MAO-A inhibitor PDB code (2Z5X) by in-silico techniques [68]. The strategy for the design was to modify the flavanone (C6-C3-C6 three ring skeleton) to benzoflavanone composes naphthalene in spite of the first C6 ring.…”

(E)-1-(1-Hydroxynaphthalen-2-yl)-3-(2,4,5-trimethoxyphenyl)prop-2-en-1-one

“…(Hans et al 2010). In continuation of our research interest to develop benzochalcone derivatives which show broad range of biological activities (Jo et al 2012), titled compound was synthesized and its crystal structure was determined.…”