کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
443533 692731 2011 15 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی تئوریک و عملی
پیش نمایش صفحه اول مقاله
Relaxed complex scheme suggests novel inhibitors for the lyase activity of DNA polymerase beta
چکیده انگلیسی

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.

Figure optionsDownload high-quality image (339 K)Download as PowerPoint slideResearch highlights▶ DNA polymerase β is a promising therapeutic target for cancer treatment. ▶ We filtered the NCI diversity set, DrugBank and fragment compounds for novel pol β inhibitors. ▶ We screened the set of ∼12,500 compounds against an ensemble of 11 structures of the 8 kDa domain. ▶ Our results predicted new compounds that can bind with high affinity to the lyase active site.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular Graphics and Modelling - Volume 29, Issue 5, February 2011, Pages 702–716
نویسندگان
, ,