Background: A major class of chemotherapy drugs targets the genome of cancer cells. These DNA
damaging agents induce damage to the DNA helix, resulting in the programmed death of cancer cells. An overactivated
DNA repair mechanism in cancer cells can reduce the efficacy of these drugs, thereby eliminating their
therapeutic benefit and developing an acquired resistance to these otherwise effective drugs. A promising approach
to enhance the therapeutic window of DNA damaging agents is to target the DNA repair pathways causing this
type of resistance. Methods: Computational approaches have been applied successfully to study many of these
DNA repair mechanisms at different scales and focusing on various aspects. The ultimate goal of these studies has
been to identify the key players in developing resistance to DNA damaging agents and to design regulators for their
activities. This review covers the most important and recent computational efforts toward this goal. This includes modelling the mechanisms
involved in DNA repair and identifying novel pharmacological inhibitors for their activities. Results: We focus here mainly on the
pathways associated with an acquired drug resistance to DNA damaging agents, concentrating on the recent advances in modelling the
key mechanisms and foreseeing the future directions in this field. Conclusion: We hope that this short, yet comprehensive review can
help in discovering novel strategies to overcome the resistance effects inherent in various cancer treatments.
Keywords: DNA repair, molecular modelling, drug resistance, small molecule inhibitors, cancer chemotherapy.
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