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

DNA polymerase beta (pol beta), 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 beta is mutated in approximately 30% of tumors. These mutations further lower pol beta fidelity in DNA synthesis exposing the genome to serious mutations. These findings suggested pol beta as a promising therapeutic target for cancer treatment. More than 60 pol beta-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 similar to 9000 fragmental compounds for novel pol beta inhibitors. In this procedure we screened the set of similar to 12,500 compounds against an ensemble of 11 dominant-receptor structures representing the essential backbone dynamics of the 8 kDa domain of pol beta. 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 beta. (C) 2010 Elsevier Inc. All rights reserved.