title: Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation.
abstract: Inflammatory cytokines are key drivers of cartilage degradation in post-traumatic osteoarthritis. Cartilage degradation mediated by these inflammatory cytokines has been extensively investigated using in vitro experimental systems. Based on one such study, we have developed a computational model to quantitatively assess the impact of charged small molecules intended to inhibit IL-1 mediated cartilage degradation. We primarily focus on the simplest possible computational model of small molecular interaction with the IL-1 system-direct binding of the small molecule to the active site on the IL-1 molecule itself. We first use the model to explore the uptake and release kinetics of the small molecule inhibitor by cartilage tissue. Our results show that negatively charged small molecules are excluded from the negatively charged cartilage tissue and have uptake kinetics in the order of hours. In contrast, the positively charged small molecules are drawn into the cartilage with uptake and release timescales ranging from hours to days. Using our calibrated computational model, we subsequently explore the effect of small molecule charge and binding constant on the rate of cartilage degradation. The results from this analysis indicate that the small molecules are most effective in inhibiting cartilage degradation if they are either positively charged and/or bind strongly to IL-1α, or both. Furthermore, our results showed that the cartilage structural homeostasis can be restored by the small molecule if administered within six days following initial tissue exposure to IL-1α. We finally extended the scope of the computational model by simulating the competitive inhibition of cartilage degradation by the small molecule. Results from this model show that small molecules are more efficient in inhibiting cartilage degradation by binding directly to IL-1α rather than binding to IL-1α receptors. The results from this study can be used as a template for the design and development of more pharmacologically effective osteoarthritis drugs, and to investigate possible therapeutic options.
authors.affiliation: School of Computer Science and Software Engineering, University of Western Australia, Crawley, WA, Australia.
authors.forename: Saptarshi
authors.initials: S
authors.lastname: Kar
authors.affiliation: School of Computer Science and Software Engineering, University of Western Australia, Crawley, WA, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Smith
authors.affiliation: Department of Physics and Nanotechnology, Murdoch University, Murdoch, WA, Australia.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Gardiner
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Grodzinsky
mesh_terms: D000818:Animals; D002356:Cartilage / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D003198:Computer Simulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007375:Interleukin-1 / Q000378:metabolism*; D008962:Models, Theoretical; D010003:Osteoarthritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D007375:Interleukin-1