Design and In Silico Validation of a Novel MZF-1-Based Multi-Epitope Vaccine to Combat Metastatic Triple Negative Breast Cancer.

Immunotherapy is emerging as a potential therapeutic strategy for triple negative breast cancer (TNBC) owing to the immunogenic landscape of its tumor microenvironment. Interestingly, peptide-based cancer vaccines have garnered a lot of attention as one of the most promising cancer immunotherapy regimens. Thus, the present study intended to design a novel, efficacious peptide-based vaccine against TNBC targeting myeloid zinc finger 1 (MZF1), a transcription factor that has been described as an oncogenic inducer of TNBC metastasis. Initially, the antigenic peptides from MZF1 were identified and evaluated based on their likelihood to induce immunological responses. The promiscuous epitopes were then combined using a suitable adjuvant (50S ribosomal L7/L12 protein) and linkers (AAY, GPGPG, KK, and EAAAK) to reduce junctional immunogenicity. Furthermore, docking and dynamics analyses against TLR-4 and TLR-9 were carried out to understand more about their structural stability and integrity. Finally, the constructed vaccine was subjected to in silico cloning and immune simulation studies. Overall, the findings imply that the designed chimeric vaccine could induce strong humoral and cellular immune responses in the desired organism. In light of these findings, the final multi-epitope vaccine could be used as an effective prophylactic treatment for TNBC and may pave the way for future research.

Discovery of anaplastic lymphoma kinase inhibitors from natural product library: A holistic in silico approach.

Over the years, phytochemical compounds have shown compelling evidences in exhibiting powerful antitumor properties. Moreover, due to the lack of safety and high cost of cancer therapies, opportunities are being sought out in these compounds as an alternative treatment modality. Therefore, in the present study, 1,574 compounds from NPACT library were examined to excavate potent and nontoxic anaplastic lymphoma kinase (ALK) inhibitors. Notably, two pharmacophore hypotheses (AAAHP and DDRRR) were generated using ligand-based and energy-based techniques, respectively, to eliminate false-positive prediction in database screening. Furthermore, molecular docking and Prime MM/GBSA analysis were performed on the screened compounds to examine inhibitory activity against ALK. The analysis revealed that the two hits, namely, NPACT00018 and NPACT01077, exhibited better docking scores, binding energies, and also ensured excellent drug-likeness properties than the reference compound, crizotinib. Finally, the results were subjected to molecular dynamics studies to gain insight into the stability of these compounds in the binding pocket of ALK protein. Indeed, the useful predictions generated by the present computational models are of immense importance and could further speed up the anticancer drug development in the near future.

Drug repurposing: An approach to tackle drug resistance in S. typhimurium.

Drug resistant S. typhimurium pose important public health problem. The development of effective drugs with novel mechanism(s) of action is needed to overcome issues pertaining to drug resistance. Drug repurposing based on computational analyses is considered a viable alternative strategy to circumvent this issue. In this context, 1309 FDA-approved drugs molecules from Mantra 2.0 database were analyzed for this study, against S. typhimurium. Sixteen compounds having similar profiles of gene expression as quinolones were identified from the database, Mantra 2.0. Further, the pharmacophore characteristics of each resultant molecule were identified and compared with the features of nalidixic acid, using the PharamGist program. Subsequently, the activities of these compounds against S. typhimurium DNA gyrase were identified, using molecular docking study. Side effects analysis was also performed for the identified compounds. Molecular dynamics simulation was carried out for the compound to validate its binding efficiency. Further, characterization of screened compound revealed IC50 values in micromolar concentration range, of which flufenamic acid showed comparable in vitro activity alongside ciprofloxacin and nalidixic acid. Thus represent interesting starting points for further optimization against S. typhimurium infections. It may be noted that the results we have obtained are the first experimental evidence of flufenamic acid activity against S. typhimurium.