An integrated computational approach to screening of alkaloids inhibitors of TBX3 in breast cancer cell lines.

TBX3 is an ancient and evolutionarily conserved family member of T-box transcription factors that acts as a key regulator in embryonic development and organogenesis. It is often overexpressed in various epithelial and mesenchymal malignancies which has a significant impact on various hallmarks of cancer, which mainly includes senescence shunt, apoptosis, anoikis, angiogenesis, and promoting metastatic and expansion of cancer stem cells. In addition to the role of TBX3 in early breast development, a number of studies have also confirmed the amplification of TBX3 in the occurrence and development of breast cancer. To overcome a major challenge in breast cancer treatment, resistance to current anti-cancer drug, it is important to develop new drug pipeline. In this study of different alkaloid molecules, to identify potential alkaloid inhibitors of TBX3, a structure based virtual screening was done involving molecular docking, ADME, toxicity analysis, molecular dynamics simulation. From our study 5 ligands named Jervine, Diflomotecan, Camptothecin, Vincamine, and Anoniane were primarily confirmed as potential inhibitors. The followed screening manner funnels out five potential compounds that have a high scoring function that emphasizes their high binding ability along with no toxicity effects. The molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation showed that Jervine along with Diflomotecan formed the stable complexes with TBX3 which makes it obvious that these two alkaloids can be introduced into the drug development pipeline and used as a new leader to develop new effective drugs against breast cancer.Communicated by Ramaswamy H. Sarma.

A systemic study on the vulnerability and fatality of prostate cancer patients towards COVID-19 through analysis of the TMPRSS2, CXCL10 and their co-expressed genes.

A pandemic of respiratory disease named coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is reported prostate cancer patients are susceptible to COVID-19 infection. To understand the possible causes of prostate cancer patients' increased vulnerability and mortality from COVID-19 infection, we focused on the two most important agents, transmembrane protease serine subtype 2 (TMPRSS2) and the C-X-C motif 10 (CXCL10). When SARS-CoV-2 binds to the host cell via S protein-angiotensin-converting enzyme-2 receptor interaction, TMPRSS2 contributes in the proteolytic cleavage of the S protein, allowing the viral and cellular membranes to fuse. CXCL10 is a cytokine found in elevated level in both COVID-19 and cancer-causing cytokine storm. We discovered that TMPRSS2 and CXCL10 are overexpressed in prostate cancer and COVID-19 using the UALCAN and GEPIA2 datasets. The functional importance of TMPRSS2 and CXCL10 in prostate cancer development was then determined by analyzing the frequency of genetic changes in their amino acid sequences using the cBioPortal online portal. Finally, we used the PANTHER database to examine the pathology of the targeted genes. We observed that TMPRSS2 and CXCL10, together with their often co-expressed genes, are important in the binding activity and immune responses in prostate cancer and COVID-19 infection, respectively. Finally, we found that TMPRSS2 and CXCL10 are two putative biomarkers responsible for the increased vulnerability and fatality of prostate cancer patients to COVID-19.

Screening of novel alkaloid inhibitors for vascular endothelial growth factor in cancer cells: an integrated computational approach.

Vascular endothelial growth factor (VEGF) is expressed at elevated levels by most cancer cells, which can stimulate vascular endothelial cell growth, survival, proliferation as well as trigger angiogenesis modulated by VEGF and VEGFR (a tyrosine kinase receptor) signaling. The angiogenic effects of the VEGF family are thought to be primarily mediated through the interaction of VEGF with VEGFR-2. Targeting this signaling molecule and its receptor is a novel approach for blocking angiogenesis. In recent years virtual high throughput screening has emerged as a widely accepted powerful technique in the identification of novel and diverse leads. The high resolution X-ray structure of VEGF has paved the way to introduce new small molecular inhibitors by structure-based virtual screening. In this study using different alkaloid molecules as potential novel inhibitors of VEGF, we proposed three alkaloid candidates for inhibiting VEGF and VEGFR mediated angiogenesis. As these three alkaloid compounds exhibited high scoring functions, which also highlights their high binding ability, it is evident that these alkaloids can be taken to further drug development pipelines for use as novel lead compounds to design new and effective drugs against cancer.

Epitope-based universal vaccine for Human T-lymphotropic virus-1 (HTLV-1).

Human T-cell leukemia virus type 1 (HTLV-1) was the first oncogenic human retrovirus identified in humans which infects at least 10-15 million people worldwide. Large HTLV-1 endemic areas exist in Southern Japan, the Caribbean, Central and South America, the Middle East, Melanesia, and equatorial regions of Africa. HTLV-1 TAX viral protein is thought to play a critical role in HTLV-1 associated diseases. We have used numerous bio-informatics and immuno-informatics implements comprising sequence and construction tools for the construction of a 3D model and epitope prediction for HTLV-1 Tax viral protein. The conformational linear B-cell and T-cell epitopes for HTLV-1 TAX viral protein have been predicted for their possible collective use as vaccine candidates. Based on in silico investigation two B cell epitopes, KEADDNDHEPQISPGGLEPPSEKHFR and DGTPMISGPCPKDGQPS spanning from 324-349 and 252-268 respectively; and T cell epitopes, LLFGYPVYV, ITWPLLPHV and GLLPFHSTL ranging from 11-19, 163-171 and 233-241 were found most antigenic and immunogenic epitopes. Among different vaccine constructs generated by different combinations of these epitopes our predicted vaccine construct was found to be most antigenic with a score of 0.57. T cell epitopes interacted strongly with HLA-A*0201 suggesting a significant immune response evoked by these epitopes. Molecular docking study also showed a high binding affinity of the vaccine construct for TLR4. The study was carried out to predict antigenic determinants of the Tax protein along with the 3D protein modeling. The study revealed a potential multi epitope vaccine that can raise the desired immune response against HTLV-1 and be useful in developing effective vaccines against Human T-lymphotropic virus.