Identification of genetic biomarkers, drug targets and agents for respiratory diseases utilising integrated bioinformatics approaches.

Respiratory diseases (RD) are significant public health burdens and malignant diseases worldwide. However, the RD-related biological information and interconnection still need to be better understood. Thus, this study aims to detect common differential genes and potential hub genes (HubGs), emphasizing their actions, signaling pathways, regulatory biomarkers for diagnosing RD and candidate drugs for treating RD. In this paper we used integrated bioinformatics approaches (such as, gene ontology (GO) and KEGG pathway enrichment analysis, molecular docking, molecular dynamic simulation and network-based molecular interaction analysis). We discovered 73 common DEGs (CDEGs) and ten HubGs (ATAD2B, PPP1CB, FOXO1, AKT3, BCR, PDE4D, ITGB1, PCBP2, CD44 and SMARCA2). Several significant functions and signaling pathways were strongly related to RD. We recognized six transcription factor (TF) proteins (FOXC1, GATA2, FOXL1, YY1, POU2F2 and HINFP) and five microRNAs (hsa-mir-218-5p, hsa-mir-335-5p, hsa-mir-16-5p, hsa-mir-106b-5p and hsa-mir-15b-5p) as the important transcription and post-transcription regulators of RD. Ten HubGs and six major TF proteins were considered drug-specific receptors. Their binding energy analysis study was carried out with the 63 drug agents detected from network analysis. Finally, the five complexes (the PDE4D-benzo[a]pyrene, SMARCA2-benzo[a]pyrene, HINFP-benzo[a]pyrene, CD44-ketotifen and ATAD2B-ponatinib) were selected for RD based on their strong binding affinity scores and stable performance as the most probable repurposable protein-drug complexes. We believe our findings will give readers, wet-lab scientists, and pharmaceuticals a thorough grasp of the biology behind RD.

Immune epitopes identification and designing of a multi-epitope vaccine against bovine leukemia virus: a molecular dynamics and immune simulation approaches.

BACKGROUND: Bovine leukemia virus (BLV) is an oncogenic delta-retrovirus causing bovine leucosis. Studies on BLV have shown the association with human breast cancer. However, the exact molecular mechanism is neither known nor their appropriate preventative measure to halt the disease initiation and progression. In this study, we designed a multi-epitope vaccine against BLV using a computational analyses. METHODS: Following a rigorous assessment, the vaccine was constructed using the T-cell epitopes from each BLV-derived protein with suitable adjuvant and linkers. Both physicochemistry and immunogenic potency as well as the safeness of the vaccine candidate were assessed. Population coverage was done to evaluate the vaccine probable efficiency in eliciting the immune response worldwide. After homology modeling, the three-dimensional structure was refined and validated to determine the quality of the designed vaccine. The vaccine protein was then subjected to molecular docking with Toll-like receptor 3 (TLR3) to evaluate the binding efficiency followed by dynamic simulation for stable interaction. RESULTS: Our vaccine construct has the potential immune response and good physicochemical properties. The vaccine is antigenic and immunogenic, and has no allergenic or toxic effect on the human body. This novel vaccine contains a significant interactions and binding affinity with the TLR3 receptor. CONCLUSIONS: The proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat BLV infections. However, experimental evaluations are essential to validate the exact safety and immunogenic profiling of this vaccine.

Bioinformatics approaches identified dasatinib and bortezomib inhibit the activity of MCM7 protein as a potential treatment against human cancer.

Minichromosome Maintenance Complex Component 7 (MCM7) is a key component of the DNA replication licensing factor and hexamer MCM (MCM2-7) complex that regulates the DNA replication process. The MCM7 protein is associated with tumor cell proliferation that plays an important role in different human cancer progression. As the protein is highly expressed during the cancer development process, therefore, inhibition of the protein can be utilized as a treatment option for different human cancer. However, the study aimed to identify potential small molecular drug candidates against the MCM7 protein that can utilize treatment options for human cancer. Initially, the compounds identified from protein-drugs network analysis have been retrieved from NetworkAnalyst v3.0 server and screened through molecular docking, MM-GBSA, DFT, pharmacokinetics, toxicity, and molecular dynamics (MD) simulation approach. Two compounds namely Dasatinib (CID_3062316) and Bortezomib (CID_387447) have been identified throughout the screening process, which have the highest negative binding affinity (Kcal/mol) and binding free energy (Kcal/mol). The pharmacokinetics and toxicity analysis identified drug-like properties and no toxicity properties of the compounds, where 500 ns MD simulation confirmed structural stability of the two compounds to the targeted proteins. Therefore, we can conclude that the compounds dasatinib and bortezomib can inhibit the activity of the MCM7 and can be developed as a treatment option against human cancer.

Combination of QSAR, molecular docking, molecular dynamic simulation and MM-PBSA: analogues of lopinavir and favipiravir as potential drug candidates against COVID-19.

Pandemic COVID-19 infections have spread throughout the world. There is no effective treatment against this disease. Viral RNA-dependent RNA polymerase (RdRp) catalyzes the replication of RNA from RNA and the main protease (Mpro) has a role in the processing of polyproteins that are translated from the RNA of SARS-CoV-2, and thus these two enzymes are strong candidates for targeting by anti-viral drugs. Small molecules such as lopinavir and favipiravir significantly inhibit the activity of Mpro and RdRp in vitro. Studies have shown that structurally modified lopinavir, favipiravir, and other similar compounds can inhibit COVID-19 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp). In this study, lopinavir and its structurally similar compounds were chosen to bind the main protease, and favipiravir was chosen to target RNA-dependent RNA polymerase. Molecular docking and the quantitative structure-activity relationships (QSAR) study revealed that the selected candidates have favorable binding affinity but less druggable properties. To improve the druggability, four structural analogues of lopinavir and one structural analogue of favipiravir was designed by structural modification. Molecular interaction analyses have displayed that lopinavir and favipiravir analogues interact with the active site residues of Mpro and RdRp, respectively. Absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, medicinal chemistry profile, and physicochemical features were shown that all structurally modified analogues are less toxic and contain high druggable properties than the selected candidates. Subsequently, 50 ns molecular dynamics simulation of the top four docked complexes demonstrated that CID44271905, a lopinavir analogue, forms the most stable complex with the Mpro. Further MMPBSA analyses using the MD trajectories also confirmed the higher binding affinity of CID44271905 towards Mpro. In summary, this study demonstrates a new way to identify leads for novel anti-viral drugs against COVID-19. Communicated by Ramaswamy H. Sarma.

PROM1 and PROM2 expression differentially modulates clinical prognosis of cancer: a multiomics analysis.

Prominin 1 (PROM1) is considered a biomarker for cancer stem cells, although its biological role is unclear. Prominin 2 (PROM2) has also been associated with certain cancers. However, the prognostic value of PROM1 and PROM2 in cancer is controversial. Here, we performed a systematic data analysis to examine whether prominins can function as prognostic markers in human cancers. The expression of prominins was assessed and their prognostic value in human cancers was determined using univariate and multivariate survival analyses, via various online platforms. We selected a group of prominent functional protein partners of prominins by protein-protein interaction analysis. Subsequently, we investigated the relationship between mutations and copy number alterations in prominin genes and various types of cancers. Furthermore, we identified genes that correlated with PROM1 and PROM2 in certain cancers, based on their levels of expression. Gene ontology and pathway analyses were performed to assess the effect of these correlated genes on various cancers. We observed that PROM1 was frequently overexpressed in esophageal, liver, and ovarian cancers and its expression was negatively associated with prognosis, whereas PROM2 overexpression was associated with poor overall survival in lung and ovarian cancers. Based on the varying characteristics of prominins, we conclude that PROM1 and PROM2 expression differentially modulates the clinical outcomes of cancers.

Function of the SIRT3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease.

In mammals, seven members of the sirtuin protein family known as class III histone deacetylase have been identified for their characteristic features. These distinguished characteristics include the tissues where they are distributed or located, enzymatic activities, molecular functions, and involvement in diseases. Among the sirtuin members, SIRT3 has received much attention for its role in cancer genetics, aging, neurodegenerative disease, and stress resistance. SIRT3 controls energy demand during stress conditions such as fasting and exercise as well as metabolism through the deacetylation and acetylation of mitochondrial enzymes. SIRT3 is well known for its ability to eliminate reactive oxygen species and to prevent the development of cancerous cells or apoptosis. This review article provides a comprehensive review on numerous (noteworthy) molecular functions of SIRT3 and its effect on cancer cells and various diseases including Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease.