Structural modelling and in silico pharmacology of β-carboline alkaloids as potent 5-HT1A receptor antagonists and reuptake inhibitors
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Date
2022-07-26
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Publisher
Taylor & Francis
Abstract
Serotonin (5-HT) antagonists and reuptake inhibitors (SARIs) are atypical antidepressants for managing
major depressive disorder. They are oftentimes applied as adjuvants for ameliorating aftereffects of
SSRI antidepressants including insomnia and sexual dysfunction. The few available candidates of this
class including lorpiprazole and trazodone also display some daunting side effects, making a continuous
search for improved alternatives essential. Natural b-carboline alkaloids (NbCs) are interestingly
renowned with broad pharmacological spectrum against several neuropsychiatric disorders including
depression. However, their potentials as SARIs remain underexplored. In this study, 982 NbCs retrieved
from the Ambinter-Greenpharma (Amb) database were virtually screened for potent SARI alternatives
using computational and biocheminformatics approaches: homology modelling of 5-HT1A receptor,
Glide HTVS, SP and XP molecular docking, molecular dynamics (MD) simulation, ADMET and mutagenicity
predictions. The homology receptor was validated as a good representative of human 5HT1A
receptor using the RCSB structure validation and quality protocols. From the virtual screening against
the 5-HT1A receptor, Amb ligands, Amb18709727 and Amb37857532 showed higher binding affinities
by XP scores of 8.725 and 7.976 kcal/mol, and MMGBSA of 87.972 and 107.585 kcal/mol
respectively compared to lorpiprazole, a reference SARI with XP score and MMGBSA of 6.512 and
62.788 kcal/mol respectively. They maintained ideal contacts with pharmacologically essential amino
acid residues implicated in SARI mechanisms and expressed higher stability and compactness than lorpiprazole
throughout the trajectories of 100 ns MD simulation. They also displayed interesting ADME,
druggability, low toxicity and mutagenicity profiles, ideal for CNS drug prospects, thus, recommended
as putative SARI candidates for further study
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Citation
Ayipo Y. O., Alananzeh W. A., Ahmad I., Patel H., Mordi M. N.: Structural modelling and in silico pharmacology of β-carboline alkaloids as potent 5-HT1A receptor antagonists and reuptake inhibitors. Journal of Biomolecular Structure and Dynamics, 2022, 41(13), 1-18. https://doi.org/10.1080/07391102.2022.2104376