Fragment-based Drug Design For Dual Inhibitor Of Cyclooxygenase-2and5-lipoxygenase

Dual inhibitor of cyclooxygenase-2/5-lipoxygenase not only has significantadvantages in the treatment of inflammation, but also provides a new approach thetreatment of cancer, atherosclerosis, allergy and alzheimer’s disease. Although there areseveral drugs with dual inhibition in clinical research, but because the lack of study andresearch time. The drug design is more complex to consider two targets at the same time.So it is still a hot research area to develop a dual inhibitor of cyclooxygenase-2/5-lipoxygenase with novel scaffold. The aim of the research project is to design a series ofdual inhibitor of cyclooxygenase-2/5-lipoxygenase using fragment-based drug designand multiple targets focus library method. There are three parts in this dissertation.In the first part, the COXs inhibitor and5-LOX inhibitor compounds aresummarized, and then the database of the inhibitos with structure and activities is set up.At the same time COXs enzymes database and5-LOX enzymes database are also set up.Then a molecular fragment database are built from the inhibitor databases. It provide afoundation for the fragment based drug design.In the second part, the virtual screening models of5-LOX and COX-1,COX-2arebuilt. And then pharmaceutical mechanism of inhibitors and the key hydrogen bondinginteraction between the target and inhibitors are studied.In the third part, the combinatorial library is designed through the LD1.0based onmolecular fragment. Then the huge virtual combinatorial library (133*278*278) whichis proceeded in the first part is optimized to create a focus library, which composed of8*10*10molecules. The important rules of optimization are as follows:1）the active ofcompounds which is evaluated by the virtual models setted up in the second part;2）molecular druglikeness of compounds;3）structural diversity of the focuse library.Finally of the final focused library is analyzed by the scaffold of compounds and thebinding conformation in the vitual screening. The known inhibitors are found in thelibrary, so the reliability of the focused library is confirmed. And the novel structures inthe library will be used to develop new dual inhibitor of cyclooxygenase-2/5-lipoxygenase in the future.