Computational Insights into β-Carboline Inhibition of Monoamine Oxidase A

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 beta-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 beta-carboline binding to MAO-A. The results presented herein could be applied in the rational structure-based design and optimization of beta-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.

Automated summary

In this study, we conducted computational and dynamic analysis to investigate the binding between a series of substituted beta-carboline natural products and MAO-A enzyme. The results provide important insights for rational structure-based drug design and optimization, particularly in the treatment of mental disorders such as depression.