Computational High Throughput Screening Targeting DNA Repair Proteins To Improve Cancer Therapy

• Author / Creator

  Barakat, Khaled H.

• Developing a new drug is a complex, highly structured, and expensive task. The further a potential drug progresses in the development process, the more costly its failure becomes. Virtual screening (VS) is the initial stage of a drug discovery process. Its job is to screen large compound databases for bioactive molecules. Its role is critical to reduce the probability of late-stage expensive failures. A reliable VS protocol would identify a diversity of lead compounds that are suitable for further structural optimizations. Most of the current available protocols fail at integrating the target flexibility or suggesting accurate ranking for the selected top hits. Here, we introduce an improved virtual screening protocol. A protocol that improves over current methodologies by employing complementary techniques comprising molecular docking, molecular dynamics simulations, iterative clustering techniques, principle component analysis and accurate scoring methods. The implemented VS protocol identified novel compounds that can bind to a number of important cancer-related targets. The targets chosen here play critical roles in tumor cell initiation and progression and their regulation promises for the improvement of current cancer therapy. Two of these important targets are DNA repair proteins that are linked to the hallmark “relapse” or “drug resistance” phenomena. These are Excision Repair Cross-Complementation Group 1 (ERCC1), and DNA polymerase beta (pol β). The former is a key player in Nucleotide Excision Repair (NER), while the latter is the error-prone polymerase of Base Excision Repair (BER). The third target is p53, a guardian of the genome that is inactivated in more than half of all human cancers. The work presented here has an outstanding significance on both the methods and their applications. On one hand the implemented protocol is generic and can be used almost against any target. On the other hand, the compounds we identified have the promise of being successful potential drug candidates that can progress through the drug discovery process and improve cancer therapy.

• Subjects / Keywords

  • P53
  • NER
  • Virtual Screening
  • ERCC1
  • In Silico
  • Drug Design
  • DNA pol beta
  • DNA repair
  • Inhibitors
  • MDM2
  • MDM4

• Graduation date

  Spring 2012

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3XS86

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.