Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta
DNA polymerase beta (pol ?), 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 ? is mutated in approximately 30% of tumors. These mutations further lower pol ? fidelity in DNA synthesis exposing the genome to serious mutations. These findings suggested pol ? as a promising therapeutic target for cancer treatment. More than 60 pol ?-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 ? 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 8kDa domain of pol ?. 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 ?.
dna pol ? ionizing radiation bleomycin monofunctional alkylating agents and cisplatin virtual screening drugbank fragment pamoic acid ber clustering nci database