title: Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta.
abstract: 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.
authors.affiliation: Department of Physics, University of Alberta, Edmonton, AB, Canada. kbarakat@ualberta.ca
authors.forename: Khaled
authors.initials: K
authors.lastname: Barakat
authors.forename: Jack
authors.initials: J
authors.lastname: Tuszynski
mesh_terms: D001665:Binding Sites; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D016208:Databases, Factual; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008024:Ligands; D008190:Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009154:Mutation; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D019951:DNA Polymerase beta; D008190:Lyases