Computational insights into β-carboline inhibition of monoamine oxidase A

Prah, Alja (author), Gavranić, Tanja (author), Perdih, Andrej (author), Sollner Dolenc, Marija (author), Mavri, Janez (author)

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.

• Language: English
• Keywords: monoamine oxidase, β-carbolines, depression, linear interaction energy
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 20 str.
• Numbering: Vol. 27, iss. 19, art. 6711
• PID: 20.500.12556/RUL-141864
• UDC: 616.895.4:616-085
• ISSN on article: 1420-3049
• COBISS.SI-ID: 124842499
• Publication date in RUL: 10.10.2022

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: monoaminooksidaza, β-karbolini, energija linearne interakcije, depresija (medicina)

Projects

• Funder: ARRS - Slovenian Research Agency
• Project number: P1-0012-2019
• Name: Molekulske simulacije, bioinformatika in načrtovanje zdravilnih učinkovin