Liu Yang1, Weihang Li2, Yingjing Zhao2, Sheng Zhong3, Xinhui Wang4, Shanshan Jiang5, Ye Cheng6, Haiyang Xu7, Gang Zhao8. 1. Ultrasound Department, China-Japan Union Hospital of Jilin University, Changchun, China. 2. College of Clinical Medicine, Jilin University, Changchun, China. 3. Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China; Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 4. Department of Oncology, the First Hospital of Jilin University, Changchun, China. 5. College of Pharmacy, Jilin University, Changchun, China. 6. Department of Neurosurgery, Xuan Wu Hospital of Capital Medical University, Beijing, China. 7. Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China. Electronic address: xuhaiyang_jdyy@126.com. 8. Department of Neurosurgery, the First Hospital of Jilin University, Changchun, China.
Abstract
OBJECTIVE: To screen ideal lead compounds from a drug library (ZINC15 database) with potential inhibition effect against O6-methylguanine-DNA methyltransferase (MGMT) to contribute to medication design and refinement. METHODS: 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 LibDock scores, followed by absorption, distribution, metabolism, and 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 stability of the ligand-MGMT complex under natural circumstances. RESULTS: Two novel natural compounds, ZINC000008220033 and ZINC000001529323, from the ZINC15 database were found to bind with MGMT with a higher binding affinity together with more favorable interaction energy. Also, they were predicted to have less rodent carcinogenicity, Ames mutagenicity, and developmental toxicity potential as well as noninhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis demonstrated that the 2 complexes ZINC000008220033-MGMT and ZINC000001529323-MGMT had more favorable potential energy compared with reference ligand O6-benzylguanine, and they could exist stably in the natural environment. CONCLUSIONS: This study elucidated that ZINC000008220033 and ZINC000001529323 were ideal lead compounds with potential inhibition targeting to MGMT protein. These compounds were selected as safe drug candidates and may contribute a solid basis for MGMT target medication design and improvement.
OBJECTIVE: To screen ideal lead compounds from a drug library (ZINC15 database) with potential inhibition effect against O6-methylguanine-DNA methyltransferase (MGMT) to contribute to medication design and refinement. METHODS: 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 LibDock scores, followed by absorption, distribution, metabolism, and 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 stability of the ligand-MGMT complex under natural circumstances. RESULTS: Two novel natural compounds, ZINC000008220033 and ZINC000001529323, from the ZINC15 database were found to bind with MGMT with a higher binding affinity together with more favorable interaction energy. Also, they were predicted to have less rodent carcinogenicity, Ames mutagenicity, and developmental toxicity potential as well as noninhibition with cytochrome P-450 2D6. Molecular dynamics simulation analysis demonstrated that the 2 complexes ZINC000008220033-MGMT and ZINC000001529323-MGMT had more favorable potential energy compared with reference ligand O6-benzylguanine, and they could exist stably in the natural environment. CONCLUSIONS: This study elucidated that ZINC000008220033 and ZINC000001529323 were ideal lead compounds with potential inhibition targeting to MGMT protein. These compounds were selected as safe drug candidates and may contribute a solid basis for MGMT target medication design and improvement.