The emerging monkeypox virus (MPXV) is a zoonotic orthopoxvirus that causes infections in humans similar to smallpox. Since May 2022, cases of monkeypox (MPX) have been increasingly reported by the World Health Organization (WHO) worldwide. Currently, there are no clinically validated treatments for MPX infections. In this study, an immunoinformatics approach was used to identify potential vaccine targets against MPXV. A total of 190 MPXV-2022 proteins were retrieved from the ViPR database and subjected to various analyses including antigenicity, allergenicity, toxicity, solubility, IFN-γ, and virulence. Three outer membrane and extracellular proteins were selected based on their respective parameters to predict B-cell and T-cell epitopes. The epitopes are conserved among different strains of MPXV and the population coverage is 100% worldwide, which will provide broader protection against various strains of the virus globally. Nine overlapping MHC-I, MHC-II, and B-cell epitopes were selected to design multi-epitope vaccine constructs linked with suitable linkers in combination with different adjuvants to enhance the immune responses of the vaccine constructs. Molecular modeling and structural validation ensured high-quality 3D structures of vaccine constructs. Based on various immunological and physiochemical properties and docking scores, MPXV-V2 was selected for further investigation. In silico cloning revealed a high level of gene expression for the MPXV-V2 vaccine within the bacterial expression system. Immune and MD simulations confirmed the molecular stability of the MPXV-V2 construct, with high immune responses within the host cell. These results may aid in the development of experimental vaccines against MPXV with increased potency and improved safety.

Cancer is a major cause of death, affecting human life in both developed and developing countries. Numerous antitumor agents exist but their toxicity and low efficacy limits their utility. Furthermore, the complex pathophysiological mechanisms of cancer, serious side effects and poor prognosis restrict the administration of available cancer therapies. Thus, developing novel therapeutic agents are required towards a simultaneous targeting of major dysregulated signaling mediators in cancer etiology, while possessing lower side effects. In this line, the plant kingdom is introduced as a rich source of active phytochemicals. The secondary metabolites produced by plants could potentially regulate several dysregulated pathways in cancer. Among the secondary metabolites, flavonoids are hopeful phytochemicals with established biological activities and minimal side effects. Flavonoids inhibit B-cell lymphoma 2 (Bcl-2) via the p53 signaling pathway, which is a significant apoptotic target in many cancer types, hence suppressing a major dysregulated pathway in cancer. To date, there have been no studies reported which extensively highlight the role of flavonoids and especially the different classes of flavonoids in the modulation of Bcl-2 in the P53 signaling pathway. Herein, we discuss the modulation of Bcl-2 in the p53 signaling pathway by different classes of flavonoids and highlight different mechanisms through which this modulation can occur. This study will provide a rationale for the use of flavonoids against different cancers paving a new mechanistic-based approach to cancer therapy.

Staphylococcus lugdunensis is a coagulase-negative, Gram-positive, and human pathogenic bacteria. S. lugdunensis is the causative agent of diseases, such as native and prosthetic valve endocarditis, meningitis, septic arthritis, skin abscesses, brain abscess, breast abscesses, spondylodiscitis, post-surgical wound infections, bacteremia, and peritonitis. S. lugdunensis displays resistance to beta-lactam antibiotics due to the production of beta-lactamases. This study aimed to identify potential novel essential, human non-homologous, and non-gut flora drug targets in the S. lugdunensis strain N920143, and to evaluate the potential inhibitors of drug targets. The method was concerned with a homology search between the host and the pathogen proteome. Various tools, including the DEG (database of essential genes) for the essentiality of proteins, the KEGG for pathways analysis, CELLO V.2.5 for cellular localization prediction, and the drug bank database for predicting the druggability potential of proteins, were used. Furthermore, a similarity search with gut flora proteins was performed. A DNA-binding response-regulator protein was identified as a novel drug target against the N920143 strain of S. lugdunensis. The three-dimensional structure of the drug target was modelled and validated with the help of online tools. Furthermore, ten thousand drug-like compounds were retrieved from the ZINC15 database. The molecular docking approach for the DNA-binding response-regulator protein identified ZINC000020192004 and ZINC000020530348 as the most favorable compounds to interact with the active site residues of the drug target. These two compounds were subjected to an MD simulation study. Our analysis revealed that the identified compounds revealed more stable behavior when bound to the drug target DNA-binding response-regulator protein than the apostate.

Despite continual efforts being made with multiple clinical studies and deploying cutting-edge diagnostic tools and technologies, the discovery of new cancer therapies remains of severe worldwide concern. Multiple drug resistance has also emerged in several cancer cell types, leaving them unresponsive to the many cancer treatments. Such a condition always prompts the development of next-generation cancer therapies that have a better chance of inhibiting selective target macromolecules with less toxicity. Therefore, in the present study, extensive computational approaches were implemented combining molecular docking and dynamic simulation studies for identifying potent pyrazole-based inhibitors or modulators for CRMP2, C-RAF, CYP17, c-KIT, VEGFR, and HDAC proteins. All of these proteins are in some way linked to the development of numerous forms of cancer, including breast, liver, prostate, kidney, and stomach cancers. In order to identify potential compounds, 63 in-house synthesized pyrazole-derivative compounds were docked with each selected protein. In addition, single or multiple standard drug compounds of each protein were also considered for docking analyses and their results used for comparison purposes. Afterward, based on the binding affinity and interaction profile of pyrazole compounds of each protein, potentially strong compounds were filtered out and further subjected to 1000 ns MD simulation analyses. Analyzing parameters such as RMSD, RMSF, RoG and protein–ligand contact maps were derived from trajectories of simulated protein–ligand complexes. All these parameters turned out to be satisfactory and within the acceptable range to support the structural integrity and interaction stability of the protein–ligand complexes in dynamic state. Comprehensive computational analyses suggested that a few identified pyrazole compounds, such as M33, M36, M72, and M76, could be potential inhibitors or modulators for HDAC, C-RAF, CYP72 and VEGFR proteins, respectively. Another pyrazole compound, M74, turned out to be a very promising dual inhibitor/modulator for CRMP2 and c-KIT proteins. However, more extensive study may be required for further optimization of the selected chemical framework of pyrazole derivatives to yield improved inhibitory activity against each studied protein receptor.