Computational Study of Novel Natural Inhibitors Targeting O-Methylguanine-DNA Methyltransferase.

Objective: To screen ideal lead compounds from a drug library (ZINC15 database) with potential inhibition effect against O-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 O-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.