Computational study on novel natural inhibitors targeting c-MET
| Autor: | Gaojing Dou, Junan Ren, Xinhui Wang, Yuanyuan Hou, Junliang Ge, Jing Wang, Zhiyun Zhang, Baolin Zhou, Wenzhuo Yang, Juncheng Li, Haoqun Xie |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Drug
C-Met Databases Factual discovery studio media_common.quotation_subject Developmental toxicity Drug Evaluation Preclinical Observational Study tivantinib Computational biology Molecular Dynamics Simulation Ligands chemistry.chemical_compound Drug Delivery Systems Distribution (pharmacology) Medicine Humans Cytotoxicity Inhibitory effect media_common c-MET business.industry glioblastoma General Medicine Proto-Oncogene Proteins c-met Ligand (biochemistry) virtual screening chemistry Toxicity business Research Article |
| Zdroj: | Medicine |
| ISSN: | 1536-5964 |
| Popis: | This study was designed to select ideal lead compounds and preclinical drug candidates http://dict.youdao.com/w/eng/preclinical_drug_candidate/javascript:void (0); with inhibitory effect on c-MET from the drug library (ZINC database). A battery of computer-aided virtual techniques was used to identify possible inhibitors of c-MET. A total of 17,931 ligands were screened from the ZINC15 database. LibDock is applied for structure-based screening followed by absorption, distribution, metabolic, and excretion, and toxicity prediction. Molecular docking was conducted to confirm the binding affinity mechanism between the ligand and c-MET. Molecular dynamics simulations were used to assess the stability of ligand-c-MET complexes. Two new natural compounds ZINC000005879645 and ZINC000002528509 were found to bind to c-MET in the ZINC database, showing higher binding affinity. In addition, they were predicted to have lower rodent carcinogenicity, Ames mutagenicity, developmental toxicity potential, and high tolerance to cytochrome P4502D6. Molecular dynamics simulation shows that ZINC000005879645 and ZINC000002528509 have more favorable potential energies with c-MET, which could exist stably in the natural environment. This study suggests that ZINC000005879645 and ZINC000002528509 are ideal latent inhibitors of c-MET targeting. As drug candidates, these 2 compounds have low cytotoxicity and hepatotoxicity as well as important implications for the design and improvement of c-MET target drugs. |
| Databáze: | OpenAIRE |
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