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.

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.