Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta

J Mol Graph Model. 2011 Feb;29(5):702-16. doi: 10.1016/j.jmgm.2010.12.003. Epub 2010 Dec 13.


DNA polymerase beta (pol β), the error-prone polymerase of base excision repair, plays a significant role in chemotherapeutic agent resistance. Its over expression reduces the efficacy of anticancer drug therapies including ionizing radiation, bleomycin, monofunctional alkylating agents and cisplatin. Small-scale studies on different types of cancer showed that pol β is mutated in approximately 30% of tumors. These mutations further lower pol β fidelity in DNA synthesis exposing the genome to serious mutations. These findings suggested pol β as a promising therapeutic target for cancer treatment. More than 60 pol β-inhibitors have been identified so far, however, most of them are either not potent or specific enough to become a drug. Here, we applied the relaxed complex scheme virtual screening (RCSVS) to allow for the full receptor flexibility in filtering the NCI diversity set, DrugBank compounds and a library of ∼ 9000 fragmental compounds for novel pol β inhibitors. In this procedure we screened the set of ∼ 12,500 compounds against an ensemble of 11 dominant-receptor structures representing the essential backbone dynamics of the 8 kDa domain of pol β. Our results predicted new compounds that can bind with higher affinity to the lyase active site compared to pamoic acid (PA), a well-known inhibitor of DNA pol β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • DNA Polymerase beta / antagonists & inhibitors*
  • DNA Polymerase beta / chemistry*
  • DNA Polymerase beta / genetics
  • Databases, Factual
  • Enzyme Inhibitors / chemistry*
  • Ligands
  • Lyases / antagonists & inhibitors*
  • Lyases / chemistry*
  • Lyases / genetics
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Mutation
  • Principal Component Analysis
  • Protein Structure, Tertiary*


  • Enzyme Inhibitors
  • Ligands
  • DNA Polymerase beta
  • Lyases