COMPUTER AIDED DRUG DESIGNING FOR COMBINATORIAL IMMUNOTHERAPEUTICS

Abstract

Cancer is one of the leading causes of adult deaths worldwide. Chemotherapy, radiation therapy, immunotherapy, hormonal therapy and surgical removal of tumors are the most common clinical approaches being used for the treatment of cancer. Today, there are more than 100 FDA approved drugs in the markets for cancer therapy. Unfortunately, the chemotherapy treatment is almost always accompanied by a varied range of short and long term adverse effects. Also the cancerous cells evolve and develop resistance against these drugs during the course of treatment to escape the process of cell death and sustain their survival. Hence, the need arises to explicate the various molecular mechanisms which get altered and support the survival of transformed cells. This would help us find novel targets highly specific to tumor or cancer cells and design drugs against them. Since natural compounds offer a potentially infinite source of chemical diversity which cannot be matched by any synthetic chemical collection or combinatorial chemistry approach, in this study we have used in silico methods to identify small molecule natural compounds with inhibitory activity against cancer specific molecular targets. Firstly, we have used a series of 4-methylpyridopyrimidinone derived PI3K inhibitors to develop a 3D-QSAR model which was then used to screen a dataset of natural compounds to predict more potent PI3K inhibitors. In complex diseases like cancer, single target approach sometimes do not result in desired outcome as the transformed cells find for an alternate pathway to compensate for the loss. In such cases, multi target approach is more efficient for a significant modification in the environment of cancer cells. With this perspective in mind, secondly we have proposed another natural compound with potential to simultaneously inhibit three cancer specific targets- Fatty acid synthase, Phosphatidylinositol 3-kinase (p110α) and Skp2 component of SCF E3 Ubiquitin Ligase. Lastly, we have reported a molecule of natural origin that shows the ability to stimulate body’s own immune system to fight against cancerous cells by activating NK cells through TLR3 receptor.