Low-density lipoprotein receptor-related protein 6 (LRP6) is an important therapeutic target for diseases such as osteoporosis, Alzheimer, cancer, and neurodegenerative disease. Computational methods such as ligand-based and structure-based virtual screening have been introduced as an extremely efficient and accurate tool for finding new drug targets and candidates. In this study, we aimed to screen the National Cancer Institute (NCI) Diversity Set II and parts of the ZINC database by virtual screening to identify potential and safe compounds that can inhibit the LRP6 protein. By utilizing various screening methods such as rigid and flexible molecular docking and Lipinski’s rule of five, we identified 10 potential compounds. Then, their validity was further tested by molecular dynamics simulation and MMPBSA binding free energy calculations. Eventually, it was concluded that ZINC03954520, ZINC01729523, ZINC03898665, ZINC13152226, ZINC26730911 and ZINC01069082 compounds can be potential drug compounds for inhibiting LRP6 protein. These compounds in complex with β-propeller domains of LRP6 showed that they are capable of altering the backbone of these domains and interfere with their structural dynamics which may lead to the inhibition of the signal transmission. Communicated by Ramaswamy H. Sarma

Regarding the urgency of therapeutic measures for coronavirus disease 2019 (COVID-19) pandemic, the use of available drugs with FDA approval is preferred because of the less time and cost required for their development. In silico drug repurposing is an accurate way to speed up the screening of the existing FDA-approved drugs to find a therapeutic option for COVID-19. The similarity in SARS-CoV-2 and HIV-1 fusion mechanism to host cells can be a key point for Inhibit SARS-CoV-2 entry into host cells by HIV fusion inhibitors. Accordingly, in this study, an HIV-1 fusion inhibitor called Enfuvirtide (Enf) was selected. The affinity and essential residues involving in the Enf binding to the S2 protein of SARS-CoV-2, HIV-1 gp41 protein and angiotensin-converting enzyme 2 (ACE-2) as a negative control, was evaluated using molecular docking. Eventually, Enf-S2 and Enf-gp41 protein complexes were simulated by molecular dynamics (MD) in terms of binding affinity and stability. Based on the most important criteria such as docking score, cluster size, energy and dissociation constant, the strongest interaction was observed between Enf with the S2 protein. In addition, MD results confirmed that Enf-S2 protein interaction was remarkably stable and caused the S2 protein residues to undergo the fewest fluctuations. In conclusion, it can be stated that Enf can act as a strong SARS-CoV-2 fusion inhibitor and demonstrates the potential to enter the clinical trial phase of COVID-19. Communicated by Ramaswamy H. Sarma

Monkeypox virus is a member of the Poxviridae family, which causes monkeypox zoonotic disease. Since July 2022, the prevention of monkeypox have become more considerable due to the new outbreak, making it a global concern. Therefore, we used an in silico-based method, including immunoinformatics, bioinformatics, molecular docking, and gene cloning approaches to design a novel multiepitope vaccine against monkeypox. Three immunogenic envelope proteins of monkeypox virus, including G10R, E8L, and A30L, were selected to predict appropriate immune system stimulator epitopes. The A30L is common between smallpox and monkeypox virus, so the proposed vaccine may be effective against smallpox too. There is no evidence of allergenicity and toxicity of the vaccine epitopes. To boost the immunogenicity of the designed vaccine, we used the helper epitope of PADRE and RS01as adjuvants. Furthermore, some linkers are used to link epitopes and adjuvants together. The physicochemical futures of the designed vaccine were assessed. The tertiary structure of the vaccine was modeled and then refined to improve its structure and physicochemical properties. To analyze the vaccine construct and TLR4 complex affinity, they were docked to gather. Besides, the vaccine was cloned into E.coli. pET-21b(+) plasmid to reveal that it can be expressed and stimulate the immune system. Immune stimulation evaluation showed that the candidate vaccine could induce the production of IgM, IgG1, and IgG2 antibodies. Overall, we suggested an effective vaccine candidate against monkeypox. However, Future studies and clinical trials should be done to ensure the efficacy and safety of this vaccine. Communicated by Ramaswamy H. Sarma

Introduction. Streptococcus pneumoniae is a significant bacterial pathogen in humans. Currently, there are two types of pneumococcal vaccines, but there are concerns regarding their application. Aim. Since many pneumococcal proteins are serotype-independent, polyhistidine triad protein D (PhtD) has been selected as a vaccine candidate. Methodology. We prepared recombinant PhtD and its C-terminal fragment (PhtD-C) using alum and outer-membrane vesicles (OMVs) as adjuvants. The combinations were injected intraperitoneally into mice, and then total immunoglobulin G (IgG) and specific IgG, IgG1 and IgG2a were measured. A serum bactericidal assay and opsonophagocytosis were also performed as complementary tests. Meningococcal OMVs were used as an adjuvant. Results. The levels of specific IgG and IgG1 against combinations of PhtD and its C-terminal with OMVs and alum as adjuvants increased at the time of the third mouse immunization on day 35. Forty per cent and 60% of S. pneumoniae ATCC 6303 (serotype 3) as a virulent pneumococcal strain, respectively, were killed in the opsonophagocytosis test and these results could also be observed in the serum bactericidal assay. Mice mmunized iwith PhtD and its C-terminal with OMVs and alum as adjuvants survived after 10 days of pneumococcal challenge. Conclusion. The combination of PhtD and PhtD-C with alum produced optimal results, but the combination of PhtD and PhtD-C with OMVs produced minimal results by comparison. The survival rates were also measured, and these corresponded with the results of the immunological assessments. Our findings showed that mice receiving PhtD and PhtD-C plus OMV and alum had higher survival rates than the mice in the other groups.

Human T-cell leukemia virus type I (HTLV-1) belongs to the delta retrovirus family and the etiological agent of adult T-cell leukemia (ATL(. While the current HTLV-1 therapy, relies on using Zidovudine plus IFN-γ, there is no FDA approved drugs against it. In silico drug repurposing is a fast and accurate way for screening US-FDA approved drugs to find a therapeutic option for the HTLV-1 infection. So that, this research aims to analyze a dataset of approved antiviral drugs as a potential prospect for an anti-viral drug against HTLV-1 infection. Molecular docking simulation was performed to identify interactions of the antiviral drugs with the key residues in the HTLV-1 protease binding site. Then, molecular dynamics simulation was also performed for the potential protein-ligand complexes to confirm the stable behavior of the ligands inside the binding pocket. The best docking scores with the target was found to be Simeprevir, Atazanavir, and Saquinavir compounds which indicate that these drugs can firmly bind to the HTLV-1 protease. The MD simulation confirmed the stability of Simeprevir-protease, Atazanavir-Protease, and Saquinavir-Protease interactions. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against HTLV-1 infection. Communicated by Ramaswamy H. Sarma