Bornyl (3,4,5-trihydroxy)-cinnamate - An optimized human neutrophil elastase inhibitor designed by free energy calculations

Human neutrophil elastase (HNE), a serine protease, is involved in the regulation of inflammatory processes and controlled by endogenous proteinase inhibitors. Abnormally high levels of HNE can cause degradation of healthy tissues contributing to inflammatory diseases such as rheumatoid arthritis, and also psoriasis and delayed wound healing. In continuation of our research on HNE inhibitors we have used the recently developed binding mode model for a group of cinnamic acid derivative elastase inhibitors and created bornyl (3,4,5-trihydroxy)-cinnamate. This ligand exhibited improved binding affinity predicted by means of free energy calculations. An organic synthesis scheme for the ligand was developed and its inhibitory activity was tested toward the isolated enzyme. Its IC50 value was found to be three times lower than that of similar compounds, which is in line with the computational result showing the high potential of free energy calculations as a tool in drug development.

The binding affinity of bornyl (3,4,5-trihydroxy)-cinnamate was predicted by thermodynamic integration calculations. A synthesis protocol was developed for the ligand and its inhibitory effect was tested against the isolated enzyme.Figure optionsDownload as PowerPoint slide