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Table of Contents
Year : 2021  |  Volume : 7  |  Issue : 3  |  Page : 377-382

Molecular docking-based research on the potential anti-encephalopathy effect of gentianine

1 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
2 Department of Pharmacy, COMSATS University Islamabad, Lahore, Pakistan
3 School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing; The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China

Date of Submission18-Oct-2020
Date of Acceptance30-Nov-2020
Date of Web Publication9-Aug-2021

Correspondence Address:
Dr. Chuan-Hong Wu
Beijing University of Chinese Medicine, Beijing; The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao
Dr. Na Wang
Beijing University of Chinese Medicine, Beijing
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/wjtcm.wjtcm_3_21

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Objective: Encephalopathy is increasingly threatening human health. It is correspondingly one of the concerns of society and medical community. As a natural source, traditional Chinese medicine has tremendous beneficial outcomes in various diseases including encephalopathy. Gentianine, a Chinese herbal compound, shows effectiveness in many diseases exclusively in inflammation. Therefore, this in vitro research was carried out to find its effectiveness in encephalopathy. Methodology: Ligand and proteins were searched and downloaded from ChemDraw and protein database, respectively. Sybyl-X2.0 docking software and its various functions were used to prepare ligand and proteins. Finally, gentianine was docked with proteins using Sybyl-X2.0 docking software. Results: Gentianine was docked with 20 protein targets. Compounds with C-score of 5 were selected. A total of three kinds of protein docked with gentianine (ABCC1, C-reactive protein [CRP], and NKX5-2) were selected. ABCC1 was expressed in the brain and was related to seizures and stroke. CRP was an inflammatory biomarker and related to seizures, epilepsy, stroke, and Parkinson's disease. NKX2–5 was also known as cardiac transcription and related to cerebral palsy, Alzheimer's disease, and stroke. All these targets were related to encephalopathy. Conclusion: Molecular docking findings in this study lead to the suggestion that gentianine might be helpful in treating encephalopathy. This study is expected to provide a solution to find potential anti-encephalopathy compounds.

Keywords: Encephalopathy, gentianine, molecular docking

How to cite this article:
Wahab A, Chen JX, Jia CX, Murtaza G, Wu CH, Wang N. Molecular docking-based research on the potential anti-encephalopathy effect of gentianine. World J Tradit Chin Med 2021;7:377-82

How to cite this URL:
Wahab A, Chen JX, Jia CX, Murtaza G, Wu CH, Wang N. Molecular docking-based research on the potential anti-encephalopathy effect of gentianine. World J Tradit Chin Med [serial online] 2021 [cited 2022 Aug 8];7:377-82. Available from: https://www.wjtcm.net/text.asp?2021/7/3/377/323489

  Introduction Top

Encephalopathy refers to disease with abnormal brain tissue structure and physiological functions,[1] such as brain atrophy,[2] seizures,[3] cerebral palsy,[4] Alzheimer's disease,[5] Parkinson's disease,[6] epilepsy,[7] sequelae of cerebral thrombosis,[8] and stroke hemiplegia.[9] The etiology of the above-mentioned encephalopathy is not only attributed to cranial nerve but also to cerebrovascular functions.[10] Due to the particularity of the blood–brain barrier and the complexity of the encephalopathy pathogenesis,[11],[12] the research and development of drugs for encephalopathy[13] has become a challenge in the medical community.[14],[15]

Traditional Chinese medicine (TCM) is mainly playing a vital role as a supplementary or alternative therapy in health-care systems and becoming well known in various countries. In the ancient medical system, Traditional Chinese herbal products were described as a therapy for encephalopathy.[16],[17],[18] Pharmacological studies have revealed that certain TCMs[19] have effects on anti-inflammatory,[20] antioxidant,[21] vasodilation,[22] anti-glutamic acid,[23] antiplatelet,[24] and have potential effects against encephalopathy.[25]

Gentianine is basically a pure alkaloid, which is isolated from Radix Gentianae Macrophy. Gentianine has been used for the treatment of various types of diseases such as anti-inflammatory,[26] antipyretic,[27] diuretic,[28] antidiabetic,[29] analgesic,[30] sedative-hypnotic,[31] antimutagenicity,[32] hepatic injury,[33] arthritis,[34] and antiphlogistic.[35] However, there are few literatures related to gentianine showing efficacy against encephalopathy.

Molecular docking is an in silico method for drug designing, based on structural molecular biology.[36] The objective of docking is to predict fit optimization of ligand to the tri-dimensional protein structure.[37] The key function of docking is effectively search high-dimensional spaces and correct ranking of interaction (ligand-protein) based on scoring function. It allows screening of compounds, results based on ranking and structural prediction (how a protein target can be inhibited by ligand molecule) which helps in optimizing and developing new compounds.[38] The current study aims to explore the potential anti-encephalopathy effect of gentianine based on molecular docking.

  Methodology Top

Symptom-disease network of gentianine using SymMap

SymMap (https://www.symmap.org/) is a database which shows interrelations among herb, ingredient, TCM symptom, modern medicine symptom (MM symptom), target, and disease. In this study, we used the database to construct a symptom–disease network of gentianine.

Protein preparation

The targeted proteins Protein data bank identification (PDB-ID) and their gene names, as shown in [Table 1], were downloaded from the protein database. Molecular dynamics simulation (1000fs) was applied to these complexes using SYBL-X software. SYBL-X is a docking software based on network pharmacology, which permits molecular pathway maps and docking simulation to identify ligand role in complex proteins.[39] Before docking, the structural optimization and energy minimization of the selected proteins were processed into active capsules (processing including removal of excess chains, excess small molecules, excess water molecules, and addition of hydrogen).
Table 1: Targeted genes and their gene names

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Binding analysis

For further screening the interactions between encephalopathy-related human protein targets and gentianine, Sybyl X2.0 by tripos international Certara company, USA was used for docking. Default docking parameters were selected and the C-score was considered as the criteria for active sites and ligand affinity. C-score is the sum of separate terms (Van der Waals interaction, H-bonding, de-solvation effects, etc.) which explains its contributions to binding.[40] The C-score is worth to be considered from 0 to 5, where 5 indicates good affinity, 3 and 4 indicate further consideration, and 0 indicates unstable binding.

  Results and Discussion Top

Gentianine is basically a pure alkaloid, which is isolated from the Radix Gentianae Macrophy. According to SymMap, the TCM symptom-MM symptom–disease network of gentianine was constructed, as shown in [Figure 1]. Radix Gentianae Macrophy associated with encephalopathy, such as epileptic encephalopathy, Parkinsonism-dystonia, Aβ amyloidosis, and seizures. These encephalopathies were connected with three MM symptoms (fever convulsions, hemiparesis, and stroke) and three TCM symptoms (infantile fever, stroke, and hemiplegia). The network suggested that gentianine might have a potential effect on encephalopathy. However, the specific correlation between gentianine and encephalopathy remains unclear.
Figure 1: Traditional Chinese medicine symptom-MM symptom–disease network of gentianine

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Structure of gentianine was downloaded from the PubChem database, as shown in [Figure 2]. Overall, 20 protein crystal structures were downloaded from the PDB database, and their binding scores were obtained according to the surflex-dock function in Sybyl-X2.0 software. The docking results and PDB-ID are shown [Table 2].
Table 2: The docking scores of gentianine and encephalopathy-related proteins

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Figure 2: Two-dimensional structure of gentianine

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It can be seen from the above table that ABCC1, C-reactive protein (CRP), and NKX2-5 have a good affinity with gentianine. The docking of gentianine with ABBC1 showed a good C-score of 5 and two hydrogen bonds at TRP16 and ARG780, as shown in [Figure 3]. According to reports, ABCC1 (multi-drug resistance-associated protein 1) was expressed in the brain and can mildly downregulated in response to focal cerebral ischemia and seizures.[41] Kilic et al. reported that ABCC1 acts as a transporter for pharmacological active compound to the brain. Binding of pharmacologically active compounds to abluminal ABC transporter facilitates drug therapy.[41] Binding of gentianine to ABCC1 might facilitate the transportation of various pharmacologically active compounds through the blood–brain barrier into the brain.
Figure 3: Gentianine docking to ABCC1

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CRP docking with gentianine also gave us a high docking score of 5 and one hydrogen bond at GLU85, as shown in [Figure 4]. CRP is an inflammatory biomarker associated with a high risk of seizures, epilepsy, stroke, and Parkinson's disease.[42] Tian et al. study showed that CRP links to transient ischemic stroke or cerebrovascular attack.[43] CRP is an acute-phase protein, its level increases in various inflammatory states.[44] Various reports illustrated that during ischemia, there is an increased level of inflammatory mediators and CRP.[45] High levels of CRP relate to various vascular events like cerebrovascular accident and myocardial infarction, as reported in various studies. An earlier study demonstrated an elevated level of CRP during encephalopathy[46] (seizures, epilepsy, stroke, and Parkinson's disease) which, in turn, causes further inflammation and brain injury.[47] Inflammation acts a vital role in physiopathology of encepalopathy.[48]
Figure 4: Gentianine docking to C-reactive protein

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Gentianine was docked with NKX2-5 with a docking score of 5 and one hydrogen bond at ARG190, as shown in [Figure 5]. NKX2-5 (homeobox protein NKX-2.5) also known as cardiac transcription and it was identified to play a role in stroke, cerebral palsy, and Alzheimer's disease.[49] Binding of gentianine to NKX2-5 provided clues that gentianine might be effective in treating encephalopathy.
Figure 5: Gentianine docking to NKX2-5

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All the protein targets of Gentianine obtained through molecular docking and their activity in various pathological condition as shoen in [Figure 6].
Figure 6: Gentianine molecular docking network loop

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  Conclusion Top

Gentianine has a good affinity with ABCC1, CRP, and NKX2-5, which suggests that gentianine might have a great potential in the treatment of encephalopathy. However, limitations of the effects of gentianine still remain to be explored. These three target proteins are in three different aspects and related to different types of encephalopathy. Further pharmacological experiments were needed to provide further evidence for gentianine in the treatment of encephalopathy in future.

Financial support and sponsorship

This work was supported by the National Natural Science Foundation of China (No. 82004085), the Double First-Class Personnel Office-Research Fund of Scientific Research Team (1000061020051), University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (UNPYSCT-2018032), and Chunhui program from Ministry of Education (HLJ2019039).

Conflicts of interest

Prof. Jian-Xin Chen is an editorial Board member of World Journal of Traditional Chinese Medicine. The article was subject to the journal's standard procedures, with peer review handled independently of this editorial board member and their research groups.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]

  [Table 1], [Table 2]

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