Identification of Potential Inhibitors from Medicinal Plant-based Phytochemicals for the Influential C4 Target of Diabetic Retinopathy by Molecular Docking Studies

Article

Author: Murugesan, Sankaranarayanan ; Alagarsamy, Veerachamy ; Sulthana, Mohaideen Thasthagir ; Muzaffar-Ur-Rehman, Mohammed ; Solomon, Viswas Raja ; Narendhar, Bandi ; Chandu, Ala ; Satishchandra, Aithamraju ; Kulkarni, Vishaka Sumant

Introduction:Diabetic retinopathy is the major cause of vision failure in diabetic patients, and the current treatment involves the practice of glucocorticoids or VEGF antagonists that are “off-label”. A few small organic molecules against DR were discovered many years ago. Nutraceuticals are naturally available functional foods that endorse different health benefits, including vitamins, antioxidants, minerals, fatty acids, and amino acids that can defer the development of some diseases.Methods:Numerous studies reported that nutraceuticals encourage multiple therapeutic benefits and provide protection against various diseases. In diabetes, nutraceuticals contribute to improving insulin sensitivity, metabolism regulation, and lower hyperglycemia. The major aim of this study is to discover the most active drug from natural or plant sources. In this work, 42 phytochemical constituents from 4 kinds of plants were docked with the C4 target of diabetic retinopathy by an in silico molecular docking study.Results:According to the binding energy, all the phytoconstituents possessed good to high attraction towards the target, and 6 phytochemicals, such as terchebulin, punicalagin, chebulagic acid, casuarinin, punicalin, and pedunculagin, disclosed superior binding energy towards the target than standard ruboxistaurin via the interactions of conventional hydrogen bonding, pi-alkyl interactions, etc. Molecular dynamic simulation studies further established the stability of the phytoconstituents, and ADMET studies proved the safety profile of these phytoconstituents.Conclusion:Hence, the current study suggested that the phytochemicals from various herbs inhibit the C4 target of diabetic retinopathy and can be utilized as lead compounds to develop analogs or repurposed for the treatment of DR.

17 Dec 2024·Journal of Virology

Both chebulagic acid and punicalagin inhibit respiratory syncytial virus entry via multi-targeting glycoprotein and fusion protein

Article

Author: Xiong, Yingcai ; Zhang, Zhaowei ; Cao, Peng ; Tao, Keyu ; Ou, Weiying ; Ji, Jianjian ; Hou, Yayi ; Zhou, Yinghui ; Wang, Shouchuan ; Wang, Zhao ; Li, Tao

ABSTRACT Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections, with no currently available small-molecule drugs that are both safe and effective. A major obstacle in antiviral drug development is the rapid emergence of drug-resistant viral strains. Targeting multiple viral compounds may help mitigate the development of resistance. Herein, we conducted a drug screening using the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to identify compounds that simultaneously target the RSV fusion (F) protein, glycoprotein (G), and the host heparan sulfate proteoglycans (HSPGs). From this screening, 10 candidate compounds were identified for their ability to interact with all three targets. Among these 10 candidates, chebulagic acid (CHLA) and punicalagin (PUG) demonstrated the most potent inhibition of RSV replication. In vitro dose–response assays confirmed the antiviral efficacy of CHLA (IC50: 0.07864 µM) and PUG (IC50: 0.08065 µM). Further experiments revealed both CHLA and PUG disrupt RSV attachment and membrane fusion by targeting the RSV-F and G proteins, rather than HSPG. Notably, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with docking assays predicting their binding sites at cysteines 176 and 182. Additionally, CHLA enhanced the conformational stability of the RSV-F protein before fusion. In an in vivo study, both CHLA and PUG were shown to alleviate RSV-induced pulmonary pathology by reducing viral titers, mitigating lung injury, and suppressing the inflammatory responses in the lungs. Our findings suggest that CHLA and PUG hold potential as therapeutic agents for RSV infection. IMPORTANCE A significant challenge in developing anti-respiratory syncytial virus (RSV) agents is the rapid emergence of resistant viral strains. Designing drugs that target multiple viral components can effectively reduce the likelihood of developing resistant strains. In this study, we screened compounds from the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to simultaneously targe the RSV fusion (F) protein, glycoprotein (G), and host heparan sulfate proteoglycans (HSPGs). Our findings revealed that chebulagic acid (CHLA) and punicalagin (PUG) significantly inhibited RSV replication both in vitro and in vivo and interacted with all three targets. Both CHLA and PUG were able to disrupt RSV attachment and membrane fusion. Mechanistically, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with CHLA also enhancing the conformational stability of the RSV-F protein before fusion. In conclusion, our study suggests that CHLA and PUG hold promise as therapeutic agents against RSV infection.

01 Nov 2024·Journal of Chromatography A

An integrated strategy for deciphering quality markers of Terminaliae Belliricae Fructus based on a three-dimensional characteristic model

Article

Author: Xu, Yi-Han ; Chen, Juan ; Chen, Xin-Yue

Terminalia bellirica (Gaertn.) Roxb. is an ethnomedicinal plant that has been utilized in Tibetan and traditional Chinese medicine (TCM). Nevertheless, its quality standard officially listed in the Chinese Pharmacopoeia does not include any content determination of the indicator components of Terminaliae Belliricae Fructus, which constrains the effective quality evaluation of medicinal material and related products. In this paper, a three-dimensional "content-pharmacokinetics-pharmacology" network strategy was developed to identify the quality markers (Q-markers) of Terminaliae Belliricae Fructus in terms of "measurability", "traceability" and "effectiveness". Chromatographic fingerprint analysis was performed to outline its chemical contour, and identify the differential components of 17 batches of Terminaliae Belliricae Fructus combined with multivariate statistics analysis and UPLC-QTOF-MS analysis. Serum pharmacochemistry analysis was implemented on rats, and 25 prototype components absorbed into the blood were identified. By network pharmacology analysis, a component-disease-target-pathway network was constructed, thus validating the effectiveness of the chemical components of Terminaliae Belliricae Fructus. Afterwards, the above screened candidate components were put into construction of three-dimensional "radar chart". According to the calculated regression area (RA) and coefficient of variation (CV) values, the potential Q-markers was determined, followed by "specificity" evaluation. Ultimately, ellagic acid (EA), chebulagic acid (CHA), gallic acid (GA), chebulinic acid (CA), corilagin (CO) and chebulanin (CH) were specified as the Q-markers of Terminaliae Belliricae Fructus. Owing to high content, good pharmacokinetic property, high pharmacological activities and specificity. The screened Q-markers could offer a scientific foundation for the quality control of Terminaliae Belliricae Fructus, and the proposed strategy is demonstrated to be reliable and feasible for deciphering Q-markers of TCM.

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Indication	Highest Phase	Country/Location	Organization	Date
Influenza A virus infection	Preclinical	CA	Simon Fraser University	24 Jun 2020

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