Screening of phytoconstituents of Andrographis paniculata against various targets of Japanese encephalitis virus: An in-silico and in-vitro target-based approach
01 Jan 2021-Vol. 2, pp 100043
TL;DR: In this paper, andrographolide has shown a good binding affinity towards NS3 protease as compared to NS3 helicase and NS5 Rdrp (RNA dependent RNA polymerase) of Japanese encephalitis virus.
Abstract: Japanese encephalitis (JE) is one of the viral diseases affecting millions of peoples across the globe specifically developing countries. There is no specific treatment available, however, vaccines are available for its prevention. Unfortunately, available vaccines are not effective against all clinical isolates and are also associated with neurological complications in some individuals. We have screened the selected phytoconstituents of Andrographis paniculata against various targets of Japanese encephalitis virus (JEV) using Schrodinger suite 2019-3. Among all selected phytoconstituents, andrographolide has shown a good binding affinity towards NS3 protease as compared to NS3 helicase and NS5 Rdrp (RNA dependent RNA polymerase) of JEV. The molecular dynamics (MD) results have also shown good stability of andrographolide in the active site of NS3 protease. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis has also indicated a good pharmacokinetic and safety profile of andrographolide. Finally, the in-vitro target-based assay have confirmed the inhibitory potential of andrographolide against the NS3 protease of JEV. In conclusion, andrographolide could have the potential to develop as an antiviral agent against JEV through inhibition of protease, however, further investigations are required.
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TL;DR: Results showed considerable stability and intermolecular interaction with native ligand-binding site residues of JEV–RdRp protein and can be considered for future antiviral drug development studies.
Abstract: The Japanese encephalitis virus (JEV), a mosquito-borne flavivirus that causes viral encephalitis leading to neural damage, is a major threat in most Asian countries. The RNA-dependent RNA polymerase (RdRp) present in the viral genome is the key component for genome replication, making it an attractive target for antiviral drug development. In this study, the natural products from Echinacea angustifolia were retrieved for structure-based virtual screening against JEV–RdRp. The top six compounds (Echinacoside, Echinacin, Rutin, Cynaroside, Quercetagetin 7-glucoside, and Kaempferol-3-glucoside) were obtained based on the highest negative docking score, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and molecular interaction. The computational analysis of these selected compounds against the co-crystallized ligands, i.e., ATP and GTP, were performed. Further, 100 ns molecular dynamic simulation and post-free binding energy calculation of all the selected compounds complexed with JEV–RdRP were performed to check the stability of the complexes. The obtained results showed considerable stability and intermolecular interaction with native ligand-binding site residues of JEV–RdRp. Hence, selected natural compounds are admissible inhibitors of JEV–RdRp protein and can be considered for future antiviral drug development studies.
4 citations
TL;DR: In this article , the association of antiviral drugs and their possible mechanism with eosinophilia and systemic symptoms (DRESS) syndrome was investigated using data mining algorithms such as proportional reporting ratio (PRR) with associated χ2 value (>4), reporting odds ratio (ROR) with 95% confidence interval and case count (≥3) to identify a possible signal.
Abstract: Antiviral drugs are not known for drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The current study aims is to find out the association of antiviral drugs and their possible mechanism with DRESS. Data mining algorithms such as proportional reporting ratio that is, PRR (≥2) with associated χ2 value (>4), reporting odds ratio that is, ROR (≥2) with 95% confidence interval and case count (≥3) were calculated to identify a possible signal. Further, molecular docking studies were conducted to check the interaction of selected antiviral drugs with possible targets. The potential signal of DRESS was found to be associated with abacavir, acyclovir, ganciclovir, lamivudine, lopinavir, nevirapine, ribavirin, ritonavir, and zidovudine among all selected antiviral drugs. Further, subgroup analysis has also shown a potential signal in different age groups and gender. The sensitivity analysis results have shown a decrease in the strength of the signal, however, there was no significant impact on the outcome except for acyclovir. The docking results have indicated the possible involvement of human leukocyte antigen (HLA)*B1502 and HLA*B5801. The positive signal of DRESS was found with selected antiviral drugs except for acyclovir.
2 citations
TL;DR: In this paper , a systematic review highlights the current status of efforts put in to develop antivirus drugs against Japanese encephalitis and the available vaccines, along with their effectiveness, and summarizes epidemiology, structure, pathogenesis, and potential drug targets that can be explored to develop a new range of anti-JEV drugs to combat JEV infection globally.
Abstract: Japanese encephalitis virus (JEV) is the causal agent behind Japanese encephalitis (JE), a potentially severe brain infection that spreads through mosquito bites. JE is predominant over the Asia-Pacific Region and has the potential to spread globally with a higher rate of morbidity and mortality. Efforts have been made to identify and select various target molecules essential in JEV’s progression, but until now, no licensed anti-JEV drug has been available. From a prophylactic point of view, a few licensed JE vaccines are available, but various factors, viz., the high cost and different side effects imposed by them, has narrowed their global use. With an average occurrence of >67,000 cases of JE annually, there is an urgent need to find a suitable antiviral drug to treat patients at the acute phase, as presently only supportive care is available to mitigate infection. This systematic review highlights the current status of efforts put in to develop antivirals against JE and the available vaccines, along with their effectiveness. It also summarizes epidemiology, structure, pathogenesis, and potential drug targets that can be explored to develop a new range of anti-JEV drugs to combat JEV infection globally.
1 citations
TL;DR: An overview of antivirus drugs that target Japanese encephalitis (JE) elements and host factors is presented in this paper , and drugs that balance antiviral effects and host protection by regulating innate immunity, inflammation, apoptosis, or necrosis are reviewed to treat JE effectively.
Abstract: Culex mosquitoes are the primary vectors of the Japanese encephalitis virus (JEV). Since its discovery in 1935, Japanese encephalitis (JE), caused by JEV, has posed a significant threat to human health. Despite the widespread implementation of several JEV vaccines, the transmission chain of JEV in the natural ecosystem has not changed, and the vector of transmission cannot be eradicated. Therefore, JEV is still the focus of attention for flaviviruses. At present, there is no clinically specific drug for JE treatment. JEV infection is a complex interaction between the virus and the host cell, which is the focus of drug design and development. An overview of antivirals that target JEV elements and host factors is presented in this review. In addition, drugs that balance antiviral effects and host protection by regulating innate immunity, inflammation, apoptosis, or necrosis are reviewed to treat JE effectively.
TL;DR: Sarma et al. as mentioned in this paper performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyridylate derivatives to stabilize inactive confirmation of hTS.
Abstract: Human thymidylate synthase is the rate-limiting enzyme in the de novo synthesis of 2'-deoxythymidine-5'-monophosphate. dUMP (pyrimidine) and folate binding site hTS inhibitors showed resistance in colorectal cancer (CRC). In the present study, we have performed virtual screening of the pyrido[2,3-d]pyrimidine database, followed by binding free energy calculations, and pharmacophore mapping to design novel pyrido[2,3-d]pyrimidine derivatives to stabilize inactive confirmation of hTS. A library of 42 molecules was designed. Based on the molecular docking studies, four ligands (T36, T39, T40, and T13) were identified to have better interactions and docking scores with the catalytic sites [dUMP (pyrimidine) and folate binding sites] of hTS protein than standard drug, raltitrexed. To validate efficacy of the designed molecules, we performed molecular dynamics simulation studies at 1000 ns with principal component analysis and binding free energy calculations on the hTS protein, also drug likeness properties of all hits were in acceptable range. Compounds T36, T39, T40, and T13 interacted with the catalytic amino acid (Cys195), an essential amino acid for anticancer activity. The designed molecules stabilized the inactive conformation of hTS, resulting in the inhibition of hTS. The designed compounds will undergo synthesis and biological evaluation, which may yield selective, less toxic, and highly potent hTS inhibitors.Communicated by Ramaswamy H. Sarma.
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