Article ; Online: Fenugreek steroidal saponins hinder osteoclastogenic bone resorption by targeting CSF-1R which diminishes the RANKL/OPG ratio.
International journal of biological macromolecules
2021 Volume 186, Page(s) 351–364
Abstract: Osteoporosis is skeletal fragility caused by the excessive bone resorption due to osteoclastogenesis. But current drugs are less bioavailable and possess higher toxicity. Our study was conducted to identify safe oral bioavailable drugs from Fenugreek ... ...
| Abstract | Osteoporosis is skeletal fragility caused by the excessive bone resorption due to osteoclastogenesis. But current drugs are less bioavailable and possess higher toxicity. Our study was conducted to identify safe oral bioavailable drugs from Fenugreek steroidal saponins and to delineate underlying mechanism of them to lower the osteoclastogenic bone resorption. We observed higher molecular docked binding affinities in finally selected eight hit compounds within the range of -11.0 to -10.1 kcal/mol which was greater than currently used drugs. Molecular Dynamics simulation with Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Solvent Accessible Surface Area (SASA) and Gyration trajectory projection reinforced the stability of the protein-ligand complexes. Pharmacokinetics analysis confirmed bioavailability of seven compounds out of eight, and drug likeliness and bioavailability profile evaluation indicated that they all are eligible to be developed as a potent oral inhibitor of CSF-1R. By literature mining knowledge-driven analysis, RNAseq data and Molecular Dynamics Simulation, we proposed that, the hit derivatives block the CSF-1/CSF-1R induced phosphorylation signaling pathway in both osteoclast and osteoblast resulting in hindrance of RANK expression and formation of Reactive oxygen species (ROS) in osteoclast and osteoblast respectively, thus declines the RANKL/OPG ratio, lowering the osteoclast survival, proliferation and differentiation. |
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| MeSH term(s) | Administration, Oral ; Biological Availability ; Bone Density Conservation Agents/administration & dosage ; Bone Density Conservation Agents/isolation & purification ; Bone Density Conservation Agents/pharmacokinetics ; Bone Density Conservation Agents/pharmacology ; Databases, Genetic ; Humans ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Osteoblasts/drug effects ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Osteoclasts/drug effects ; Osteoclasts/metabolism ; Osteoclasts/pathology ; Osteoporosis/metabolism ; Osteoporosis/pathology ; Osteoporosis/prevention & control ; Osteoprotegerin/metabolism ; Plant Extracts/administration & dosage ; Plant Extracts/isolation & purification ; Plant Extracts/pharmacokinetics ; Plant Extracts/pharmacology ; RANK Ligand/metabolism ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Saponins/administration & dosage ; Saponins/isolation & purification ; Saponins/pharmacokinetics ; Saponins/pharmacology ; Signal Transduction ; Structure-Activity Relationship ; Trigonella/chemistry |
| Chemical Substances | Bone Density Conservation Agents ; CSF1R protein, human ; Osteoprotegerin ; Plant Extracts ; RANK Ligand ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ; Saponins ; TNFRSF11B protein, human ; TNFSF11 protein, human |
| Language | English |
| Publishing date | 2021-07-01 |
| Publishing country | Netherlands |
| Document type | Journal Article |
| ZDB-ID | 282732-3 |
| ISSN | 1879-0003 ; 0141-8130 |
| ISSN (online) | 1879-0003 |
| ISSN | 0141-8130 |
| DOI | 10.1016/j.ijbiomac.2021.06.197 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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