Cells have the ability to find errors and repair DNA during the cell cycle. Errors in replication, if not repaired, may lead to cancer. If the error is not repairable, the cell will actually signal itself to perform apoptosis, programmed cell death. If these errors are allowed to propagate, the chances of oncogenesis increase. These DNA mechanisms are investigated for potential cancer therapeutics.
Research involves designing AGT inhibitors that supplement chemotherapy, as various alkylating agents are used to induce DNA damage. Most of these alkyl lesions are mutagenic and can be highly cytotoxic as secondary effects. Eventually cells have evolved with various mechanisms to detect and repair DNA damage, resulting in therapeutic resistance.
O6-alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein that acts in a single step to restore DNA with O6-Alkylguanine lesions, and thus prevents mutations and apoptosis arising from alkylated guanines. A novel strategy is explored to reverse this drug resistance by inhibiting the DNA repair pathways to enhance chemo and radio sensitivity.
Research is aimed at generating a refined protein through Macromodel conformational studies and molecular dynamic simulations, later validating the protein model by cross docking and correlation studies with known inhibitors. Thus generating a reliably predictive model in the design of more potent inhibitors by virtual screening of commercially available compounds to identify potential new lead compounds. Later pursue lead optimization studies using Combiglide taking into consideration, virtual ADME properties using QuikProp from Schrodinger suite along with biological in vivo assay studies to confirm the activity of lead hits.
PDB 1T38: Human o6-alkylguanine-DNA alkyltransferase bound to DNA containing o6-methylguanine.