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Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors.

ABSTRACT: Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABA_A receptors (GABA_ARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC₅₀ of 31.5 ± 1.7 and 40.6 ± 8.2 μM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABA_ARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.

SUBMITTER: Marileo AM

PROVIDER: S-EPMC10970644 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors.

Marileo Ana M AM Lara César O CO Sazo Anggelo A Contreras Omayra V OV González Gabriel G Castro Patricio A PA Aguayo Luis G LG Moraga-Cid Gustavo G Fuentealba Jorge J Burgos Carlos F CF Yévenes Gonzalo E GE

International journal of molecular sciences 20240316 6

Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine ...[more]

PMID: 38542362

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Project description:BackgroundColorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. Gelsemium elegans Benth (GEB) is a traditional Chinese medicine commonly used for treatment for gastrointestinal cancer, including CRC. However, the underlying active ingredients and mechanism remain unknown. This study aims to explore the active components and the functional mechanisms of GEB in treating CRC by network pharmacology-based approaches.MethodsCandidate compounds of GEB were collected from the Traditional Chinese Medicine@Taiwan, Traditional Chinese Medicines Integrated Database, Bioinformatics Analysis Tool for Molecular mechanism of Traditional Chinese Medicine, and published literature. Potentially active targets of compounds in GEB were retrieved from SwissTargetPrediction databases. Keywords "colorectal cancer", "rectal cancer" and "colon cancer" were used as keywords to search for related targets of CRC from the GeneCards database, then the overlapped targets of compounds and CRC were further intersected with CRC related genes from the TCGA database. The Cytoscape was applied to construct a graph of visualized compound-target and pathway networks. Protein-protein interaction networks were constructed by using STRING database. The DAVID tool was applied to carry out Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis of final targets. Molecular docking was employed to validate the interaction between compounds and targets. AutoDockTools was used to construct docking grid box for each target. Docking and molecular dynamics simulation were performed by Autodock Vina and Gromacs software, respectively.ResultsFifty-three bioactive compounds were successfully identified, corresponding to 136 targets that were screened out for the treatment of CRC. Functional enrichment analysis suggested that GEB exerted its pharmacological effects against CRC via modulating multiple pathways, such as pathways in cancer, cell cycle, and colorectal cancer. Molecular docking analysis showed that the representative compounds had good affinity with the key targets. Molecular dynamics simulation indicated that the best hit molecules formed a stable protein-ligand complex.ConclusionThis network pharmacology study revealed the multiple ingredients, targets, and pathways synergistically involved in the anti-CRC effect of GEB, which will enhance our understanding of the potential molecular mechanism of GEB in treatment for CRC and lay a foundation for further experimental research.

Project description:Gelsemium elegans (Gardner and Champ.) Benth. (Gelsemiaceae) (GEB) is a toxic plant indigenous to Southeast Asia especially China, and has long been used as Chinese folk medicine for the treatment of various types of pain, including neuropathic pain (NPP). Nevertheless, limited data are available on the understanding of the interactions between ingredients-targets-pathways. The present study integrated network pharmacology and experimental evidence to decipher molecular mechanisms of GEB against NPP. The candidate ingredients of GEB were collected from the published literature and online databases. Potentially active targets of GEB were predicted using the SwissTargetPrediction database. NPP-associated targets were retrieved from GeneCards, Therapeutic Target database, and DrugBank. Then the protein-protein interaction network was constructed. The DAVID database was applied to Gene Ontology and Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis. Molecular docking was employed to validate the interaction between ingredients and targets. Subsequently, a 50 ns molecular dynamics simulation was performed to analyze the conformational stability of the protein-ligand complex. Furthermore, the potential anti-NPP mechanisms of GEB were evaluated in the rat chronic constriction injury model. A total of 47 alkaloids and 52 core targets were successfully identified for GEB in the treatment of NPP. Functional enrichment analysis showed that GEB was mainly involved in phosphorylation reactions and nitric oxide synthesis processes. It also participated in 73 pathways in the pathogenesis of NPP, including the neuroactive ligand-receptor interaction signaling pathway, calcium signaling pathway, and MAPK signaling pathway. Interestingly, 11-Hydroxyrankinidin well matched the active pockets of crucial targets, such as EGFR, JAK1, and AKT1. The 11-hydroxyrankinidin-EGFR complex was stable throughout the entire molecular dynamics simulation. Besides, the expression of EGFR and JAK1 could be regulated by koumine to achieve the anti-NPP action. These findings revealed the complex network relationship of GEB in the "multi-ingredient, multi-target, multi-pathway" mode, and explained the synergistic regulatory effect of each complex ingredient of GEB based on the holistic view of traditional Chinese medicine. The present study would provide a scientific approach and strategy for further studies of GEB in the treatment of NPP in the future.

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Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors.

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Molecular Pharmacology of <i>Gelsemium</i> Alkaloids on Inhibitory Receptors.

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