Computer-Aided Drug Design of DNA Repair Inhibitors Targeting the ERCC1-XPF Endonuclease

• Author / Creator

  Gentile, Francesco

• Computational methods are nowadays essential tools employed in the field of drug design. Indeed, bringing a molecular compound from bench to clinic is a challenging, time-consuming and expensive goal to achieve. Computer-aided drug design (CADD) techniques aim to simplify this process, by in-silico identifying compounds active against a critical macromolecular target. With the knowledge of the molecular structure of the compounds and preferably also of the target of interest, virtual screening can produce a high-confidence, limited set of small molecules to be tested experimentally, reducing enormously both the time and the cost otherwise required for the in-vitro screening. Computer simulations of ligand-receptor complexes provide also structural insights of the interactions which can rationally drive the hit-to-lead optimization process.In this thesis, CADD techniques are used to identify and optimize DNA repair inhibitors. Although DNA repair mechanisms are essential to maintain genome integrity in normal cells, they counteract the action of many DNA-damaging therapies used in cancer. Hence a drug able to inhibit DNA repair in cancer cells could be used in combination with these therapies to enhance their effect and reduce drug resistance effect. The nucleotide excision repair (NER) pathway, responsible for repairing bulky DNA damages, is the main focus of this thesis. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group F (XPF) heterodimer is a critical NER complex involved in repairing platinum-based chemotherapy and radiation-induced DNA damages. Hence, inhibiting the action of ERCC1-XPF, through disrupting essential protein-protein interactions or blocking the catalytic activity, is one of the most promising strategies to enhance the effects of these therapeutic approaches.iiiTherefore, the CADD effort discussed in this work has been directed towards three different aspects of ERCC1-XPF: first, the interaction between ERCC1 and the xeroderma pigmentosum, complementation group A (XPA) protein, essential to recruit the repair machinery to the damaged DNA zone. Second, the catalytic activity, performed by the active site present on the XPF surface. Last, the ERCC1-XPF heterodimerization, required to have a functional endonuclease.The results reported in this thesis are of great importance for the field of combination cancer therapy. On one hand, this work presents a number of new hit or lead compounds able to inhibit DNA repair. Thanks to the collaborative environment of the Alberta DNA Repair Consortium (of which this work is part), many of these small molecules are currently under optimization and experimental testing with the final aim to translate them to clinical use. On the other hand, detailed biophysical and structural characterization of these compounds and their binding to the targets are covered as well, opening new venues for future rational drug design works.

• Subjects / Keywords

  • ERCC1-XPF
  • cancer therapeutics
  • computer-aided drug design
  • virtual screening
  • DNA repair

• Graduation date

  Spring 2019

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-hnsp-7c04

• License

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