Research Paper Volume 14, Issue 11 pp 4874—4887
Effective natural inhibitors targeting IGF-1R by computational study
- 1 Department of Orthopaedics, The First Bethune Hospital of Jilin University, Changchun, China
- 2 Department of Radiology, Jilin Province People’s Hospital, Changchun, China
Received: September 27, 2021 Accepted: May 10, 2022 Published: June 9, 2022https://doi.org/10.18632/aging.204117
How to Cite
Copyright: © 2022 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
IGF-1R belongs to a tyrosine kinase family and is currently a newly discovered drug target. IGF-1R inhibitors can bind directly to IGF-1R to achieve the effect of inhibiting the function of IGF-1R. At present, IGF-1R inhibitors have good clinical effects on Ewing sarcoma in the clinic. In this article, we screened compounds capable of inhibiting IGF-1R function through computer-aided virtual technology. First, some molecules with good docking properties for IGF-1R can be screened by LibDock. Then, ADME analysis (adsorption, distribution, metabolism, and excretion) and toxicity indicators were performed. The mechanism of binding and the binding affinity in the middle of IGF-1R and ligand were verified using molecular docking. Ultimately, the stability of ligand-receptor complex was evaluated using molecular dynamics simulations.
In line with the results, two natural compounds ZINC000014946303 and ZINC000006003042 were found in the ZINC database, potential effective inhibitors of IGF-1R. ZINC000014946303 and ZINC000006003042 can bind to IGF-1R with high binding affinity as predicted by molecular docking. It was also found that they are not hepatotoxic, with less developmental toxicity potential, rodent carcinogenicity, Ames mutagenicity, and high tolerance to cytochrome P4502D6. Hereby, this study aimed to screen out ideal compounds that have inhibitory effects on IGF-1R from the drug library and, at the same time, provide a direction for the future development of IGF-1R inhibitors.
IGF-1R: Insulin-like growth factor 1 receptor; ADME: adsorption, distribution, metabolism and excretion; DTP: developmental toxicity potential; CYP2D6: cytochrome P4502D6; EWS-FLI1: Ewing sarcoma breakpoint region 1-friend leukemia virus integration 1; PPB: plasma protein binding; BBB: blood brain barrier; TOPKAT: toxicity prediction by Computer assistive technology; RMSD: Root Mean Square Deviation; DS4.5: Discovery Studio 4.5 software; UCSF: University of California, San Francisco; HTS: high-throughput screening; CHARMm: Chemistry at HARvard Macromolecular Mechanics; mAb: monoclonal antibody.