Current Drug Discovery Technologies - Volume 20, Issue 1, 2023

Background: One of the major problems with Brucella infections is its tendency to become chronic and recurrent, providing a hindrance to the management of this infection. It has been proposed that chronicity is greatly affected by a phenomenon called persistence in bacteria. Several mechanisms are involved in bacterial persistence, including the type II toxin-antitoxin system, the SOS and oxidative and stringent responses. Methods: In this in silico study, these persistence mechanisms in Brucella spp. were investigated. Results: The structure and the interactions between modules involved in these systems were designed, and novel peptides that can interfere with some of these important mechanisms were developed. Conclusion: Since peptide-based therapeutics are a new and evolving field due to their ease of production, we hope that peptides developed in this study, as well as the information about the structure and interactions of modules of persistence mechanisms, can further be used to design drugs against Brucella persister cells in the hope of restraining the chronic nature of Brucellosis.

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.

Background: Flavanone compounds and their related derivatives are reported in controlling cell cycle, angiogenesis, and metastasis. Phosphoinositide 3-kinases is a major drug target. Methods: Crystalize structure of Phosphoinositide 3-kinases-Akt complex obtained from Protein Data Bank (PDBID: 3CQW) was selected as receptor protein and the binding site has been identified with PDBSum Database. Flavanone and its derivatives were retrieved using freely available existing drug databases like Drug Bank, Zinc, and PubChem. New derivatives were modified by altering the flavanone at Beta ring position. This modification would help in maintaining stable structural conformation and retaining better anticancer activity. Retrieved Flavanone derivatives from the drug database were docked against 3CQW Protein with the advanced docking tool FlexX. MD simulations of the best molecule were performed with the Desmond package by calculating nonbonding interactions such as electrostatic interaction and hydrogen bond stable and favorable conformations were calculated. Results: These interaction studies would help identify new potential drug candidates with the help of computer-aided drug designing techniques. Conclusion: Natural chemicals have received a lot of attention because of their vast range of applications in human health and disease prevention without creating any negative side effects. Molecular docking is an essential approach for drug development since it allows for effective screening of potential therapeutics in a short time. We hypothesized in this paper that natural flavanone and its derivatives may be effective as Akt-1 inhibitors.

Background: The bioactive constituents from Zingiber officinale (Z. officinale) have shown a positive effect on neurodegenerative diseases like Alzheimer's disease (AD), which manifests as progressive memory loss and cognitive impairment. Objective: This study investigates the binding ability and the pharmaco-therapeutic potential of Z. officinale with AD disease targets by molecular docking and molecular dynamic (MD) simulation approaches. Methods: By coupling enormous available phytochemical data and advanced computational technologies, the possible molecular mechanism of action of these bioactive compounds was deciphered by evaluating phytochemicals, target fishing, and network biological analysis. Results: As a result, 175 bioactive compounds and 264 human target proteins were identified. The gene ontology and Kyoto Encyclopaedia of Genes and Genomes pathway enrichment analysis and molecular docking were used to predict the basis of vital bioactive compounds and biomolecular mechanisms involved in the treatment of AD. Amongst selected bioactive compounds, 10- Gingerdione and 1-dehydro-[8]-gingerdione exhibited significant anti-neurological properties against AD targeting amyloid precursor protein with docking energy of -6.0 and -5.6, respectively. Conclusion: This study suggests that 10-Gingerdione and 1-dehydro-[8]-gingerdione strongly modulates the anti-neurological activity and are associated with pathological features like amyloid-β plaques and hyperphosphorylated tau protein are found to be critically regulated by these two target proteins. This comprehensive analysis provides a clue for further investigation of these natural compounds' inhibitory activity in drug discovery for AD treatment.

Aim: The present research work aims to prepare a series of 1-(4-(2-(1H-indol-1-yl)-2- oxoethoxy)phenyl)-3-phenylprop-2-en-1-one derivatives. Methods: The major compound was achieved by the reaction of indole with chloroacetylchloride in benzene afforded 2-chloro-1-(indoline-1-yl) ethanone which reacts o- hydroxy acetophenone in presence of acetonitrile to form 2-(4-acetylphenoxy)-1-(1H-indol-1-yl)ethan-1-one then goes through aldol condensation to give various final derivatives. Results and Conclusion: After the synthesis of compounds, the synthesized compounds were characterized by checking their solubility, melting point, thin layer chromatography, IR, 1HNMR spectral data and elemental analysis. All of the prepared derivatives were evaluated for their anti-inflammatory activity on wistar albino rats by following the carrageenan-induced Rat Hind Paw Edema model.

Background: The sudden appearance of the SARS-CoV2 virus has almost changed the future of vaccine development. There have been many different approaches to vaccination; among them, computational vaccinology in the form of multi-epitope vaccines with excellent immunological properties and minimal contamination or other adverse reactions has emerged as a promising strategy with a lot of room for further study in this area. Objective: Designing a multi-epitope vaccine from the spike protein of SARS-CoV2 based on immunoinformatics and in-silico techniques. Evaluating the binding affinity of the constructed vaccine against the major variants of concern (alpha, beta, delta, and omicron) using docking studies. Methods: The potential antigenic, immunogenic, and non-allergic T-cell epitopes were thoroughly explored using IEDB, NetCTL1.2, and NetMHCII pan 3.2 servers. The best suitable linker was identified using the ExPASy Protparam tool and VERIFY 3D. The 3D model of the vaccine was developed by RaptorX and the model was validated using ERRAT, Z-score, and Ramachandran Plot. Docking studies of the vaccine with TLR-2, 3, 4, and 7 and alpha, beta, delta, and omicron variants were performed using HADDOCK 2.4. Results: The vaccine construct showed good antigenic and immunogenic scores and was non-allergic as well. The model was capable of binding to all four selected Toll-like receptors. Docking scores with variants were also promising. Conclusion: All the variants showed good binding ability with the vaccine construct. Interaction with the alpha variant was found to be the most intense, followed by delta, beta, and omicron.