机构：[1]Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China[2]Department of Oncology, the First Hospital of Jilin University, Changchun, China[3]Ultrasound Department, China-Japan Union Hospital of Jilin University, Changchun, China[4]College of Clinical Medicine, Jilin University, Changchun, China[5]College of Pharmacy, Jilin University, Changchun, China[6]Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA[7]Department of Neurosurgery, Xuan Wu Hospital of Capital Medical University, Beijing, China神经外科
This study aimed to screen ideal lead compounds from drug library (ZINC15 database) which had potential inhibition effect against O6-methylguanine-DNA methyltransferase (MGMT) and contribute in medication design and refinement.
A series of computer-aided virtual screening techniques were used to identify potential inhibitors of MGMT. Structure-based virtual screening by libdock was carried out to calculate their libdock scores, followed by ADME (Absorption, Distribution, Metabolism, Excretion) and toxicity predictions. Molecule docking was employed to demonstrate binding affinity and mechanism between the selected ligands and MGMT protein. Molecular dynamics simulation was performed to evaluate the stability of ligand-MGMT complex under natural circumstance.
Two novel natural compounds ZINC000008220033 and ZINC000001529323 from ZINC15 database were found to bind with MGMT with a higher binging affinity together with more favorable interaction energy. Also, they were predicted with less rodent carcinogenicity, ames mutagenicity and developmental toxicity potential as well as non-inhibition with cytochrome P450 2D6 (CYP2D6). Molecular dynamics simulation analysis demonstrated that these two complex ZINC000008220033- and ZINC000001529323-MGMT had more favorable potential energy compared to the reference ligand O6-Benzyl guanine (O6-BG), and they could exist stably whether in vivo or in vitro.
This study elucidated that ZINC000008220033 and ZINC000001529323 were ideal lead compounds which had potential inhibition targeting to MGMT protein. These compounds were selected as safe drug candidates and may contribute a solid basis for MGMT protein in the medication design and improvement.
Copyright ? 2019 Elsevier Inc. All rights reserved.
第一作者机构：[3]Ultrasound Department, China-Japan Union Hospital of Jilin University, Changchun, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China
推荐引用方式(GB/T 7714)：
Liu Yang,Weihang Li,Yingjing Zhao,et al.Computational Study of Novel Natural Inhibitors Targeting O6-Methylguanine-DNA Methyltransferase [J].World neurosurgery.2019,130:E294-E306.doi:10.1016/j.wneu.2019.05.264.
APA：
Liu Yang,Weihang Li,Yingjing Zhao,Sheng Zhong,Xinhui Wang...&Gang Zhao.(2019).Computational Study of Novel Natural Inhibitors Targeting O6-Methylguanine-DNA Methyltransferase .World neurosurgery,130,
MLA：
Liu Yang,et al."Computational Study of Novel Natural Inhibitors Targeting O6-Methylguanine-DNA Methyltransferase ".World neurosurgery 130.(2019):E294-E306
