Triple-negative breast cancer (TNBC) is the most aggressive among the breast cancer subtypes and poses unique therapeutic challenges due to its distinct characteristics like lack of specific therapeutic targets. TNBC demonstrates poor survival rate enhanced immunogenic characteristics and a more favorable tumor microenvironment than other breast cancer variants. Also, TNBC patients show elevated levels of programmed death ligand-1 (PD-L1) expression in contrast to non-TNBC patients. Binding of PD-L1 with PD-1 produces an inhibitory signal, resulting in suppression of T-cell. Therapeutic approaches utilizing immunotherapies against PD-L1 exhibit promising outcomes in the treatment of TNBC. Limitations like suboptimal efficacy, inadequate oral bioavailability, and associated immune-related adverse effects of antibody-mediated anti PD-1/PD-L1 therapies have necessitated the exploration of alternative therapeutic approaches. Thus, small molecules become an alternate option for PD-1/PD-L1 inhibition. In the present study, we have used virtual screening to identify potential phytochemicals from selected Indian medicinal plants as PD-L1 inhibitors. A total of 953 phytochemicals derived from eleven selected medicinal plants were initially screened through molecular docking using the PyRx tool. Among the 953 identified phytochemicals, the top 20 compounds exhibiting the highest binding affinities in docking study were selected for further analysis. Following comprehensive ADMET analyses, 2 compounds were ultimately identified as suitable candidates for a molecular dynamics (MD) simulation study. The study identified 4-hydroxychalcone and flavylium from Glycyrrhiza glabra and Catharanthus roseus, respectively as potential PD-L1 inhibitors with enhanced stability relative to the reference molecule. Both compounds also showed enhanced gastrointestinal absorption with no predicted cytotoxic and immunotoxic effects. Consequently, these compounds present promising candidates for novel PD-L1 inhibitor development in TNBC therapy. Further experimental investigations are necessary to facilitate their clinical translation.

Liver cancer is one of the deadliest cancers worldwide. There is a growing need for natural therapeutic options due to the rising global morbidity incidence of liver cancer. Due to its crucial function in angiogenesis, vascular endothelial growth factor (VEGF) signaling is considered as an ideal target for therapeutic intervention. In this in silico study, we have screened 16 microRNAs (miRNAs) that target the KDR gene, which encode VEGFR-2, and 113 natural compounds derived from Persicaria hydropiper for their anti-angiogenic properties. MicroRNA, hsa-miR-17-3p was identified with potentials of downregulating KDR gene, using several in silico tools. Two possible compounds- 6-Hydroxyluteolin and Isorhamnetin were also identified after performing ADMET profiling and molecular docking. Furthermore, 100 ns molecular dynamics simulations were run to evaluate the stability and conformational changes of protein-ligand complexes. This study identified one microRNA and two natural compounds that showed strong interaction with KDR and its encoded VEGFR-2 receptor, respectively. To validate their effectiveness as therapeutic agents against hepatocellular carcinoma, additional wet lab studies using in vitro and in vivo techniques are necessary.

Candida albicans, an opportunistic and systemic infection causing fungus, causes skin, nail, and mucosal layer lesions in healthy individuals and hospital borne catheter-related and nosocomial infections. This particular fungus exists in two distinct stages in its life cycle: yeast and hyphae. In this study, 20 signaling pathways associated with 177 proteins from C. albicans were identified to construct a PPI network. The core part of the network consisted of 165 proteins. Network topology analyses revealed that the formed PPI network is biologically robust and scale-free, with significant interactions between proteins through 19 252 shortest pathways. In this network, the top 10 hub proteins (RAS1, CDC42, HOG1, CPH1, STE11, EFG1, CEK1, HSP90, TEC1 and CST20) were identified using network analysis, which seem to be the most important proteins involved in different pathways for the development of pathogenesis and virulence. Modular analysis of the network resulted in top six sub-networks, three of which shared eight hub proteins. Ontology and functional enrichment analyses revealed that the majority of the proteins were associated with regulation of transcription by RNA polymerase II, plasma membrane and nucleic acid binding in biological processes, and cellular components and molecular functions, respectively. Enrichment analysis indicated that the proteins were mostly involved in oxidative phosphorylation and purine metabolism signaling pathways. We determined the complex web of signaling pathway involving proteins via PPI network analysis to unravel and decipher protein interactions within C. albicans to understand the complex pathogenesis processes for targeted therapeutic interferences using novel bioinformatics strategies.