Identification of Trovafloxacin, Ozanimod, and Ozenoxacin as Potent c-Myc G-Quadruplex Stabilizers to Suppress c-Myc Transcription and Myeloma Growth.
Jinyuan ZhangTao WangXiaoju GengLinlin LiuJian GaoPublished in: Molecular informatics (2022)
c-Myc is a major oncogene that is estimated to result in almost all human cancers and the c-Myc downregulation has become an attractive strategy for cancer treatment. For it is hard to design compounds that can directly interact with the c-Myc protein, the DNA G-quadruplex (G4) was discovered in its promoter region which was referred to as a potential drug target for controlling c-Myc expression. In this study, a combined strategy of molecular docking-based virtual screening, molecular dynamics (MD) simulation, and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation was conducted on the existing FDA-Approved Drugs Library, eight compounds were selected for further experimental assay. Among them, five compounds exhibited dose-dependently anticancer activities against RPMI-8226 cells with IC 50 values less than 18.4 μM. Further experiments showed that Trovafloxacin, Ozanimod, and Ozenoxacin decreased c-Myc mRNA level obviously and downregulated c-Myc expression significantly. In summary, compounds Trovafloxacin, Ozanimod, and Ozenoxacin might be regarded as new c-Myc G4 stabilizers for the treatment of c-Myc related cancers in the future.
Keyphrases
- molecular dynamics
- molecular docking
- poor prognosis
- binding protein
- induced apoptosis
- density functional theory
- endothelial cells
- molecular dynamics simulations
- cell proliferation
- dna methylation
- single molecule
- gene expression
- signaling pathway
- cell cycle arrest
- emergency department
- current status
- circulating tumor
- long non coding rna
- high throughput
- preterm infants
- cell death
- amino acid
- adverse drug
- pi k akt
- circulating tumor cells
- virtual reality
- replacement therapy