A multitier virtual screening of antagonists targeting PD-1/PD-L1 interface for the management of triple-negative breast cancer.

Immunotherapies are promising therapeutic options for the management of triple-negative breast cancer because of its high mutation rate and genomic instability. Of note, the blockade of the immune checkpoint protein PD-1 and its ligand PD-L1 has been proven to be an efficient and potent strategy to combat triple-negative breast cancer. To date, various anti-PD-1/anti-PD-L1 antibodies have been approved. However, the intrinsic constraints of these therapeutic antibodies significantly limit their application, making small molecules a potentially significant option for PD-1/PD-L1 inhibition. In light of this, the current study aims to use a high-throughput virtual screening technique to identify potential repurposed candidates as PD-L1 inhibitors. Thus, the present study explored binding efficiency of 2509 FDA-approved compounds retrieved from the drug bank database against PD-L1 protein. The binding affinity of the compounds was determined using the glide XP docking programme. Furthermore, prime-MM/GBSA, DFT calculations, and RF score were used to precisely re-score the binding free energy of the docked complexes. In addition, the ADME and toxicity profiles for the lead compounds were also examined to address PK/PD characteristics. Altogether, the screening process identified three molecules, namely DB01238, DB06016 and DB01167 as potential therapeutics for the PD-L1 protein. To conclude, a molecular dynamic simulation of 100 ns was run to characterise the stability and inhibitory action of the three lead compounds. The results from the simulation study confirm the robust structural and thermodynamic stability of DB01238 than other investigated molecules. Thus, our findings hypothesize that DB01238 could serve as potential PD-L1 inhibitor in the near future for triple-negative breast cancer patients.

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.

Envelope Glycoprotein based multi-epitope vaccine against a co-infection of Human Herpesvirus 5 and Human Herpesvirus 6 using in silico strategies.

The Human Betaherpesviruses HHV-5 and HHV-6 are quite inimical in immunocompromised hosts individually. A co-infection of both has been surmised to be far more disastrous. This can be attributed to a synergetic effect of their combined pathologies. While there have been attempts to develop a vaccine against each virus, no efforts were made to contrive an effective prophylaxis for the highly detrimental co-infection. In this study, an ensemble of viral envelope glycoproteins from both the viruses was utilized to design a multi-epitope vaccine using immunoinformatics tools. A collection of bacterial protein toll-like receptor agonists (BPTAs) was screened to identify a highly immunogenic adjuvant for the vaccine construct. The constructed vaccine was analysed using an array of methodologies ranging from World population coverage analysis to Immune simulation, whose results indicate high vaccine efficacy and stability. Furthermore, codon optimization and in silico cloning analysis were performed to check for efficient expression in a bacterial system. Collectively, these findings demonstrate the potential of the constructed vaccine to elicit an immune response against HHV-5 and HHV-6, thus supporting the viability of in vitro and in vivo studies.