Exploring the repurposing potential of telmisartan drug in breast cancer: an in-silico and in-vitro approach.

Anticancer drug resistance is one of the biggest hurdles in the treatment of breast cancer. Drug repurposing is a viable option fordeveloping novel medical treatment strategies since this method is more cost-efficient and rapid. Antihypertensive medicines have recently been found to have pharmacological features that could be used to treat cancer, making them effective candidates for therapeutic repurposing. The goal of our research is to find a potent antihypertensive drug that can be repurposed as adjuvant therapy for breast cancer. In this study, virtual screening was performed using a set of Food and Drug Administration (FDA)-approved antihypertensive drugs as ligands with selected receptor proteins (EGFR, KRAS, P53, AGTR1, AGTR2, and ACE) assuming these proteins are regarded to have a significant role in hypertension as well as breast cancer. Further, our in-silico results were further confirmed by an in-vitro experiment (cytotoxicity assay). All the compounds (enalapril, atenolol, acebutolol, propranolol, amlodipine, verapamil, doxazosin, prazosin, hydralazine, irbesartan, telmisartan, candesartan, and aliskiren) showed remarkable affinity towards the target receptor proteins. However, maximum affinity was displayed by telmisartan. Cell-based cytotoxicity study of telmisartan in MCF7 (breast cancer cell line) confirmed the anticancer effect of telmisartan. IC50 of the drug was calculated to be 7.75 µM and at this concentration, remarkable morphological alterations were observed in the MCF7 cells confirming its cytotoxicity in breast cancer cells. Based on both in-silico and in-vitro studies, we can conclude that telmisartan appears to be a promising drug repurposing candidate for the therapeutic treatment of breast cancer.

Synergistic combination of ritonavir and cisplatin as an efficacious therapy in human cervical cancer cells: a computational drug discovery and in vitro insight.

HIV-protease inhibitor Ritonavir (RTV) is a clinical-stage drug. We exhibit here the synergistic effect of RTV coupled with cisplatin as potential combination therapy for treatment of cervical cancer. Knowledge about the interaction of RTV with the high-expression signatures in cancer is limited. Therefore, we utilized computational techniques to understand and assess the drug-binding affinity and drug-target interaction of RTV with these altered protein signatures. Computational studies revealed the potential interaction ability of RTV along with few other HIV protease inhibitors against these altered cancer targets. All targets exhibited good affinity towards RTV and the highest affinity was exhibited by CYP450 3A4, PDGFR and ALK. RTV established stable interaction with PDGFR and molecular dynamics simulation confirms their frequent interaction for 300 ns. Control docking of PDGFR with standard PDGFR inhibitor exhibited lower binding affinity when compared with RTV-PDGFR complex. In search of drugs as a part of combination therapy to reduce side effects of Cisplatin, this paper further evaluated the effect of combination of RTV and Cisplatin in cervical cancer cells. We propose several combination models that combines anti-viral drug RTV and standard chemotherapeutic agent, Cisplatin to be synergistic with CI value ranging from of 0.01 to 1.14. These observations suggest that anti-viral compound (RTV) could act synergistically with Cisplatin for cervical cancer therapy. However, further studies are warranted to investigate the combinatorial mode of action of RTV and Cisplatin on different molecular pathways to have a translational outcome in cervical cancer.Communicated by Ramaswamy H. Sarma.

Therapeutic potential of autophagy activators and inhibitors in lung and breast cancer- a review.

Autophagy is a cellular process that eliminates damaged components of cytoplasm via the lysosome. Autophagy supports cells and tissues to remain healthy by recycling old or damaged cellular organelles and proteins with new ones. The breakdown products that follow are directed into cellular metabolism, where they are utilized to produce energy as well as for maintaining homeostasis and stability of the genome. In many cancers, autophagy modulation carries out a dual role in cancer development and suppression. Autophagy suppresses the proliferation of cancer cells by bringing about cell death and limiting cancer cell development, although it also promotes tumorigenesis by encouraging cancer cell growth and formation. Nevertheless, autophagy's implication in cancer remains a paradox. While several autophagy activators, and inhibitors, such as SAH-EJ2, Gefitinib, Ampelopsin hydroxychloroquine and chloroquine, are utilized to regulate autophagy in chemoprevention, the exact intrinsic system of autophagy in cancer deserves further investigation. Despite improved treatment regimens, the incidence rate of both breast and lung cancer has grown, as has the number of recurrence cases. Hence, this review offers a wide overview of autophagy's underlying role in lung and breast cancer, particularly focusing on the various autophagy activators and inhibitors in both cancers, as well as the use of various organic compounds, regular drugs, and natural products in cancer prevention and treatment.

Drug repurposing-an emerging strategy in cancer therapeutics.

Cancer is a complex disease affecting millions of people around the world. Despite advances in surgical and radiation therapy, chemotherapy continues to be an important therapeutic option for the treatment of cancer. The current treatment is expensive and has several side effects. Also, over time, cancer cells develop resistance to chemotherapy, due to which there is a demand for new drugs. Drug repurposing is a novel approach that focuses on finding new applications for the old clinically approved drugs. Current advances in the high-dimensional multiomics landscape, especially proteomics, genomics, and computational omics-data analysis, have facilitated drug repurposing. The drug repurposing approach provides cheaper, effective, and safe drugs with fewer side effects and fastens the process of drug development. The review further delineates each repurposed drug's original indication and mechanism of action in cancer. Along with this, the article also provides insight upon artificial intelligence and its application in drug repurposing. Clinical trials are vital for determining medication safety and effectiveness, and hence the clinical studies for each repurposed medicine in cancer, including their stages, status, and National Clinical Trial (NCT) identification, are reported in this review article. Various emerging evidences imply that repurposing drugs is critical for the faster and more affordable discovery of anti-cancerous drugs, and the advent of artificial intelligence-based computational tools can accelerate the translational cancer-targeting pipeline.

Functional relevance of Gedunin as a bona fide ligand of NADPH oxidase 5 and ROS scavenger: An in silico and in vitro assessment in a hyperglycemic RBC model.

Clinical evidence suggests that type 2 diabetes therapy can greatly benefit from the suppression of reactive oxygen species generation and the activation or restoration of cellular antioxidant mechanisms. In human, NADPH oxidase (NOX) is the main producer of reactive oxygen species (ROS) that supress the activity of endogenous antioxidant enzymes. In the present study, the antioxidant potential of Gedunin was studied. In silico findings reveal its strong binding affinity with NOX5 C terminal HSP90 binding site that disrupts NOX5 stability and its ability to generate ROS, leading to restoration antioxidant enzymes activities. It was found that Gedunin suppressed hyperglycaemia induced oxidative stress in an in vitro RBC model and markedly reversed glucose induced changes including haemoglobin glycosylation and lipid peroxidation. A significant restoration of activities of cellular antioxidant enzymes; superoxide dismutase, catalase and glutathione peroxidase in the presence of Gedunin revealed its ability to reduce oxidative stress. These results substantiated Gedunin as a bona fide inhibitor of human NOX5 and a ROS scavenging antioxidant with promising therapeutic attributes including its natural origin and inhibition of multiple diabetic targets.

Identification of Potential Lead Molecules for Zika Envelope Protein from In Silico Perspective.

BACKGROUND: Zika virus is the family member of flavivirus with no reported clinically approved drugs or vaccines in the market till date. This virus is spread by Aedes mosquitoes, and can also be transmitted through sexual contact or blood transfusions. There are reported medical conditions like microcephaly among new-borns delivered by infected pregnant women. The envelope protein of Zika virus is associated with virulence, tropism, mediation of receptor binding and membrane fusion. ED1-EDII domain (K1 loop pocket) is an integral part of the envelope protein and a potential drug target. In the present study, the purpose was to identify the potential lead molecules to dock against K1 loop which could be later considered as flavivirus entry inhibitors. METHODS: Multiple sequence alignment method was considered for the analysis of indels in envelope protein. Phylogenetic tree was constructed based on the alignment. Aliphatic index, GRAVY scores and hydropathy plot of the envelope proteins were calculated for the flavivirus family members. Zika envelope protein was homology modeled and considered for protein-ligand docking analysis with chemical compounds of known functions. RESULTS: As per in silico based analysis, the envelope protein of Zika virus is highly hydrophilic with the least number of amino acid deletions compared to rest of the family members. During docking studies, it was observed that compounds like NITD, compound 6, P02, Doxytetracycline and Rolitetracycline show better binding affinity with Zika envelope protein compared to dengue virus. CONCLUSION: These better binding compounds could be the promising lead molecules for Zika envelope protein which could better block the viral entry.

Computational Studies of Beta Amyloid (Aß42) with p75NTR Receptor: A Novel Therapeutic Target in Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disorder characterized by the accumulation of beta amyloid plaques (Aß) which can induce neurite degeneration and progressive dementia. It has been identified that neuronal apoptosis is induced by binding of Aß42 to pan neurotrophin receptor (p75NTR) and gave the possibility that beta amyloid oligomer is a ligand for p75NTR. However, the atomic contact point responsible for molecular interactions and conformational changes of the protein upon binding was not studied in detail. In view of this, we conducted a molecular docking and simulation study to investigate the binding behaviour of Aß42 monomer with p75NTR ectodomain. Furthermore, we proposed a p75NTR-ectodomain-Aß42 complex model. Our data revealed that, Aß42 specifically recognizes CRD1 and CRD2 domains of the receptor and formed a "cap" like structure at the N-terminal of receptor which is stabilized by a network of hydrogen bonds. These findings are supported by molecular dynamics simulation that Aß42 showed distinct structural alterations at N- and C-terminal regions due to the influence of the receptor binding site. Overall, the present study gives more structural insight on the molecular interactions of beta amyloid protein involved in the activation of p75NTR receptor.