Acute Toxicity Study of 5, 11-Dihydroindolo [3, 2-ß]carbazole as per OECD Regulatory Guidelines.

BACKGROUND: 5,11-Dihydroindolo [3, 2-ß]carbazole is one of the phytoconstituent of the Arisaema genus, which might have various important biological activities. Recently, we have predicted the antiviral potential of this phytoconstituent against the Japanese Encephalitis virus (JEV). METHODS: Thus, in the current study, the acute toxicity profile of 5, 11-dihydroindolo [3, 2-ß]carbazole as per OECD regulatory guidelines in female Wistar rats was evaluated. RESULTS: We did not find any adverse effects, mortality, and altered behaviour in animals after administration of 5, 11-dihydroindolo [3, 2-ß] carbazole at a dose of 300 and 2000 mg/Kg. Furthermore, no significant changes in physiological and haematological parameters were observed. The histopathological study of vital organs also showed no significant changes compared to the control. CONCLUSION: Based on the findings of the current investigation, 5, 11-dihydroindolo [3, 2-ß]carbazole is a safe phytoconstituent of the Arisaema genus, which can be explored for various biological activities.

Screening of phytoconstituents of Andrographis paniculata against various targets of Japanese encephalitis virus: An in-silico and in-vitro target-based approach.

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.

Computational identification of natural product leads that inhibit mast cell chymase: an exclusive plausible treatment for Japanese encephalitis.

A recent research has identified chymase, a mast cell-specific protease as an exclusive novel therapeutic target to prevent Japanese encephalitis virus (JEV) induced encephalitis. Interestingly, JEV activates mast cell specific chymase during its penetration through blood brain barrier (BBB) which eventually guide to viral encephalitis. Hence, in this study, natural chemical entities (NCE) from multiple databases (MPD3, TIPDB and MTDP) were virtually screened for their binding affinity as chymase inhibitors, a promising negotiator for prolong survival against JEV tempted encephalitis. Merged computational programs, Maestro software, QikProp, ProTox and Gromacs were applied to screen the NCEs against target receptor (PDB: 4KP0). Three hits (C00008437, C00014417 and 8141903) were identified after employing a series of sieves such as High Throughput Virtual Screening (HTVS), Standard precision (SP) and Xtra precision (XP) molecular docking simulations followed by desired pharmacokinetic-toxicity profile predictions and molecular dynamics (MD) examinations. Maestro simulations resulted in best three binding energy scores as -11.992 kcal/mol (first ranked; C00008437), -11.673 kcal/mol (second ranked; C00014417) and -11.456 kcal/mol (third ranked; 8141903), respectively. The top three hits revealed an ideal range of pharmacokinetic and toxicity descriptors values. In addition, MD simulations enabled us to confirm top hits higher selectivity toward chymase receptor. In conclusion, this might potentially represent remarkable novel classes with an effective chymase mediated treatment to combat JEV induced encephalitis, which need to justify with further detail studies.