Network pharmacology, molecular docking, and dynamics analyses to predict the antiviral activity of ginger constituents against coronavirus infection.

COVID-19 is a global pandemic that caused a dramatic loss of human life worldwide, leading to accelerated research for antiviral drug discovery. Herbal medicine is one of the most commonly used alternative medicine for the prevention and treatment of many conditions including respiratory system diseases. In this study, a computational pipeline was employed, including network pharmacology, molecular docking simulations, and molecular dynamics simulations, to analyze the common phytochemicals of ginger rhizomes and identify candidate constituents as viral inhibitors. Furthermore, experimental assays were performed to analyze the volatile and non-volatile compounds of ginger and to assess the antiviral activity of ginger oil and hydroalcoholic extract. Network pharmacology analysis showed that ginger compounds target human genes that are involved in related cellular processes to the viral infection. Docking analysis highlighted five pungent compounds and zingiberenol as potential inhibitors for the main protease (Mpro), spike receptor-binding domain (RBD), and human angiotensin-converting enzyme 2 (ACE2). Then, (6)-gingerdiacetate was selected for molecular dynamics (MD) simulations as it exhibited the best binding interactions and free energies over the three target proteins. Trajectories analysis of the three complexes showed that RBD and ACE2 complexes with the ligand preserved similar patterns of root mean square deviation (RMSD) and radius of gyration (Rg) values to their respective native structures. Finally, experimental validation of the ginger hydroalcoholic extract confirmed the existence of (6)-gingerdiacetate and revealed the strong antiviral activity of the hydroalcoholic extract with IC 50 of 2.727 µ g / ml . Our study provides insights into the potential antiviral activity of (6)-gingerdiacetate that may enhance the host immune response and block RBD binding to ACE2, thereby, inhibiting SARS-CoV-2 infection.

Studying the connection between SF3B1 and four types of cancer by analyzing networks constructed based on published research.

Splicing factor 3B subunit 1 (SF3B1) is the largest component of SF3b protein complex which is involved in the pre-mRNA splicing mechanism. Somatic mutations of SF3B1 were shown to be associated with aberrant splicing, producing abnormal transcripts that drive cancer development and/or prognosis. In this study, we focus on the relationship between SF3B1 and four types of cancer, namely myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) and breast cancer (BC). For this purpose, we identified from the Pubmed library only articles which mentioned SF3B1 in connection with the investigated types of cancer for the period 2007 to 2018 to reveal how the connection has developed over time. We left out all published articles which mentioned SF3B1 in other contexts. We retrieved the target articles and investigated the association between SF3B1 and the mentioned four types of cancer. For this we utilized some of the publicly available databases to retrieve gene/variant/disease information related to SF3B1. We used the outcome to derive and analyze a variety of complex networks that reflect the correlation between the considered diseases and variants associated with SF3B1. The results achieved based on the analyzed articles and reported in this article illustrated that SF3B1 is associated with hematologic malignancies, such as MDS, AML, and CLL more than BC. We found that different gene networks may be required for investigating the impact of mutant splicing factors on cancer development based on the target cancer type. Additionally, based on the literature analyzed in this study, we highlighted and summarized what other researchers have reported as the set of genes and cellular pathways that are affected by aberrant splicing in cancerous cells.

SARS-CoV-2 potential drugs, drug targets, and biomarkers: a viral-host interaction network-based analysis.

COVID-19 is a global pandemic impacting the daily living of millions. As variants of the virus evolve, a complete comprehension of the disease and drug targets becomes a decisive duty. The Omicron variant, for example, has a notably high transmission rate verified in 155 countries. We performed integrative transcriptomic and network analyses to identify drug targets and diagnostic biomarkers and repurpose FDA-approved drugs for SARS-CoV-2. Upon the enrichment of 464 differentially expressed genes, pathways regulating the host cell cycle were significant. Regulatory and interaction networks featured hsa-mir-93-5p and hsa-mir-17-5p as blood biomarkers while hsa-mir-15b-5p as an antiviral agent. MYB, RRM2, ERG, CENPF, CIT, and TOP2A are potential drug targets for treatment. HMOX1 is suggested as a prognostic biomarker. Enhancing HMOX1 expression by neem plant extract might be a therapeutic alternative. We constructed a drug-gene network for FDA-approved drugs to be repurposed against the infection. The key drugs retrieved were members of anthracyclines, mitotic inhibitors, anti-tumor antibiotics, and CDK1 inhibitors. Additionally, hydroxyquinone and digitoxin are potent TOP2A inhibitors. Hydroxyurea, cytarabine, gemcitabine, sotalol, and amiodarone can also be redirected against COVID-19. The analysis enforced the repositioning of fluorouracil and doxorubicin, especially that they have multiple drug targets, hence less probability of resistance.

In Silico Analysis of a Highly Mutated Gene in Cancer Provides Insight into Abnormal mRNA Splicing: Splicing Factor 3B Subunit 1K700E Mutant.

Cancer is the second leading cause of death worldwide. The etiology of the disease has remained elusive, but mutations causing aberrant RNA splicing have been considered one of the significant factors in various cancer types. The association of aberrant RNA splicing with drug/therapy resistance further increases the importance of these mutations. In this work, the impact of the splicing factor 3B subunit 1 (SF3B1) K700E mutation, a highly prevalent mutation in various cancer types, is investigated through molecular dynamics simulations. Based on our results, K700E mutation increases flexibility of the mutant SF3B1. Consequently, this mutation leads to i) disruption of interaction of pre-mRNA with SF3B1 and p14, thus preventing proper alignment of mRNA and causing usage of abnormal 3' splice site, and ii) disruption of communication in critical regions participating in interactions with other proteins in pre-mRNA splicing machinery. We anticipate that this study enhances our understanding of the mechanism of functional abnormalities associated with splicing machinery, thereby, increasing possibility for designing effective therapies to combat cancer at an earlier stage.

Combined QM/MM and Monte Carlo study for redox leveling in Mn and Fe superoxide dismutase.

Superoxide dismutases (SOD) are vital enzymes for disproportionation of superoxide molecules in mammals. Despite the high similarity between the Mn-SOD and Fe-SOD, they are inactive if the metals in the active sites are exchanged. Here, we use DFT, QM/MM and Monte Carlo sampling to optimize the crystal structure and to calculate the mid-point potential for the native and substituted Mn/Fe-SOD. The optimized DFT and QM/MM structures of the Mn-SOD show a major conformational change for the conserved TYR34 compared to the X-ray structure. These changes reduce the distance between TYR34 and Mn ion to 2.59 Å, which yields a lower reduction potential for the Mn. On contrary, there is no significant difference between optimized and crystal structures in the Fe-SOD. The calculated E m values starting from the DFT structures of the active sites show similar pattern, in good agreement with those observed experimentally. However, the calculated E m values starting with the QM/MM structures that include the whole protein are significantly higher due to the desolvation penalty. In addition, the pK a values for the water ligand in the reduced state Mn(II) and Fe(II) were calculated. The water pK a in Mn-SOD is higher than that in Fe-SOD by 3.5 pH units, which is similar to the shift measured experimentally. Finally, we investigated the role of HIS30 and the effect of its protonation state on the E m values.