Computational Insights into β-Carboline Inhibition of Monoamine Oxidase A

Abstract

Monoamine oxidases (MAOs) are an important group of enzymes involved in the degradation of neurotransmitters and their imbalanced mode of action may lead to the development of various neuropsychiatric or neurodegenerative disorders. In this work, we report the results of an in-depth computational study in which we performed a static and a dynamic analysis of a series of substituted β-carboline natural products, found mainly in roasted coffee and tobacco smoke, that bind to the active site of the MAO‑A isoform. By applying molecular docking in conjunction with structure-based pharmacophores and molecular dynamics simulations coupled with dynamic pharmacophores, we extensively investigated the geometric aspects of MAO-A binding. To gain insight into the energetics of binding, we used the linear interaction energy (LIE) method and determined the key anchors that allow productive β-carboline binding to MAO-A. The results presented herein could be applied in the rational structure-based design and optimization of β-carbolines towards preclinical candidates that would target the MAO-A enzyme and would be applicable especially in the treatment of mental disorders such as depression.

β-Carboline Alkaloids in Soy Sauce and Inhibition of Monoamine Oxidase (MAO)

“…Remarkably, β-carbolines exert various pharmacological and psychopharmacological effects, including antidepressant-like effects [ 32 , 37 , 38 , 61 , 63 ]. They alter the concentrations of brain neurotransmitters by interaction with serotonin, benzodiazepine, opioid and imidazoline receptors and also interact with MAO, kinases and cytochrome P450 enzymes [ 14 , 31 , 32 , 33 , 34 , 35 , 39 , 64 , 65 ]. The presence of these compounds in the human brain has been involved in alcoholism and addiction and they have been investigated as potential endogenous and/or environmental proneurotoxins involved in Parkinson’s disease [ 13 , 14 , 15 , 59 , 66 , 67 ].…”

“…On the other hand, new inhibitors of MAO devoid of undesirable effects might arise from naturally occurring compounds and sources. β-Carbolines are naturally occurring bioactive alkaloids that exhibit an array of pharmacological effects such as the binding to benzodiazepine, imidazoline, serotonin and opiate receptors as well as inhibition of kinases and MAO [ 14 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Some of these substances are also involved in toxicological effects [ 14 , 15 ].…”

Review of β‐carboline and its derivatives as selective MAO‐A inhibitors

“…It must not be substituted since adding substituents to the C 6 atom does not improve its capacity to inhibit MAO‐A. [ 84 ]…”

“…The coplanar aromatic rings of harmine were found to demonstrate π-π interactions with Gln215 of hMAO-A. [83] By statically and dynamically evaluating a pattern of substitutions in β-carboline from phytoconstituents that link to the active center of the MAO-A isoform, which is primarily present in roasted coffee beans and tobacco fumes, Prah et al [84] published the findings of a thorough computational investigation. The crystal structure of MAO-A with Harmine 88 which had earlier been defined (PDB code 2Z5X).…”

“…It must not be substituted since adding substituents to the C 6 atom does not improve its capacity to inhibit MAO-A. [84] 7 | CONCLUSION β-Carbolines are one of the most desired molecular entities for medicinal chemists due to their ease of synthesis and wide biological applicability. In this review, we focused on how various substituents on the β-carboline ring affect MAO-A inhibition.…”