Computational approach in searching for dual action multitarget inhibitors for osteosarcoma

Abstract

Osteosarcoma is a common primary malignant bone tumor that typically manifests in the second decade of life. This study aimed to identify osteogenic compounds that potentially serve as multitarget inhibitors for osteosarcoma. The study was a molecular docking study of nine Food and Drug Administration-approved compounds with osteogenic properties to the key membrane proteins of osteosarcoma. The ligands used were raloxifene, simvastatin, dexamethasone, risedronate, ibandronate, zoledronic acid, ascorbic acid, alendronate, and β-glycerophosphate, whereas the target proteins used were RET, fibroblast growth factor receptor 1, KIT, PDGFRA, VEGFR1, and VEGFR2. Chem3D version 15.0.0.106 was used for ligand preparation, and AutoDockTools version 1.5.6 was used for protein preparation, whereas molecular docking was conducted using AutoDock Vina. Raloxifene, simvastatin, and dexamethasone had the lowest binding activity to the target proteins. The binding affinity of raloxifene was from -8.4 to -10.0 kcal mol^-1, that of simvastatin was -8.3 to -9.2 kcal mol^-1, whereas dexamethasone ranged from -6.9 to -9.1 kcal mol^-1. Most types of interactions were hydrophobically followed by hydrogen bonding. The current study suggests that raloxifene, simvastatin, and dexamethasone have the potential to act as multitarget inhibitors for osteosarcoma with the ability to induce bone remodeling.

Keywords: Bone cancer; cancer; large bone defect; molecular docking; raloxifene; simvastatin.

Figure 1

Cartoon representation of target proteins with their binding sites from DoGSiteScorer

Figure 2

Interaction of raloxifene, simvastatin, and dexamethasone with target proteins