GITR and Targeted Small Molecules for Cancer Immunotherapy
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Vishresh Deepak
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While revolutionary cancer treatments see progress every day, cancer still remains a severe problem in our world. Immune checkpoint inhibitors, an advanced form of immunotherapy, is a treatment utilizing small molecules to override immune system checkpoints and enhance immune cell effector function. Glucocorticoid-induced TNFR-related (GITR) proteins are proteins expressed on various immune cells that can be activated to modulate cell function and impede immune cell suppression. Due to its potential role in enhancing immune system response to tumors, GITR and its ligand, GITRL, serve as strong potential drug targets for small molecules. This study aims to pre-clinically validate and screen GITR (and GITRL) as targets while identifying the most promising compounds for binding to the targets. The expensive, resource-dependent, and complex nature of drug discovery in research labs necessitates the need for a pre-clinical study. The research involves several computational methods to determine the feasibility of the target and compounds. The initial screening identifies possible binding sites on GITR and GITRL. Pharmacophore maps for GITR and GITRL were used to identify top molecular compounds for binding with GITR and GITRL. The energy of the compounds’ interactions at the potential binding sites were analyzed using SwissDock. Using the top 5 compounds for GITR with highest predicted interaction energy, drug property evaluation (ADME potential and Lipinski’s Rule validation) was conducted to further validate the compounds. The best compound for GITR was further evaluated to ensure safety and validity of compounds through toxicity prediction using ProTox 3.0. These computational methods result in the best compounds to be analyzed further clinically using both invivo and invitro methods. The results of this experiment streamline the initial screening of the targets and compounds as well as serve as the baseline for furthering immunotherapy techniques.
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Authors
Vishresh Deepak
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References:
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